Heterocyclic kinase inhibitors

ABSTRACT

Provided herein are compounds of formula (I-A), (I-B), (I-C), or (I-D), pharmaceutical compositions comprising the compounds, and methods of use thereof. The compounds provided herein modulate kinase activity, including PI3 kinase activity, and are useful for treating diseases and conditions associated with kinase activity, including diseases and conditions associated with PI3 kinase activity.

This application is a divisional application of U.S. application Ser.No. 14/222,500, filed Mar. 21, 2014, which is a continuation applicationof U.S. application Ser. No. 13/121,157, now U.S. Pat. No. 8,703,778,which is a national phase entry pursuant to 35 U.S.C. §371 ofInternational Patent Application No. PCT/US2009/005380, filed on Sep.28, 2009, which claims the benefit of U.S. Provisional ApplicationSerial No. 61/194,310, filed on Sep. 26, 2008, each of which is herebyincorporated by reference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

The activity of cells can be regulated by external signals thatstimulate or inhibit intracellular events. The process by whichstimulatory or inhibitory signals are transmitted into and within a cellto elicit an intracellular response is referred to as signaltransduction. Over the past decades, cascades of signal transductionevents have been elucidated and found to play a central role in avariety of biological responses. Defects in various components of signaltransduction pathways have been found to account for a vast number ofdiseases, including numerous forms of cancer, inflammatory disorders,metabolic disorders, vascular and neuronal diseases (Gaestel et al.Current Medicinal Chemistry (2007) 14:2214-2234).

Kinases represent a class of important signaling molecules. Kinases cangenerally be classified into protein kinases and lipid kinases, andcertain kinases exhibit dual specificities. Protein kinases are enzymesthat phosphorylate other proteins and/or themselves (i.e.,autophosphorylation). Protein kinases can be generally classified intothree major groups based upon their substrate utilization: tyrosinekinases which predominantly phosphorylate substrates on tyrosineresidues (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src,abl), serine/threonine kinases which predominantly phosphorylatesubstrates on serine and/or threonine residues (e.g., mTorC1, mTorC2,ATM, ATR, DNA-PK, Akt), and dual-specificity kinases which phosphorylatesubstrates on tyrosine, serine and/or threonine residues.

Lipid kinases are enzymes that catalyze the phosphorylation of lipids.These enzymes, and the resulting phosphorylated lipids and lipid-derivedbiologically active organic molecules, play a role in many differentphysiological processes, including cell proliferation, migration,adhesion, and differentiation. Certain lipid kinases are membraneassociated and they catalyze the phosphorylation of lipids contained inor associated with cell membranes. Examples of such enzymes includephosphoinositide(s) kinases (such as PI3-kinases, PI4-Kinases),diacylglycerol kinases, and sphingosine kinases.

The phosphoinositide 3-kinases (PI3Ks) signaling pathway is one of themost highly mutated systems in human cancers. PI3K signaling is also akey factor in many other diseases in humans. PI3K signaling is involvedin many disease states including allergic contact dermatitis, rheumatoidarthritis, osteoarthritis, inflammatory bowel diseases, chronicobstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma,disorders related to diabetic complications, and inflammatorycomplications of the cardiovascular system such as acute coronarysyndrome.

PI3Ks are members of a unique and conserved family of intracellularlipid kinases that phosphorylate the 3′—OH group onphosphatidylinositols or phosphoinositides. The PI3K family comprises 15kinases with distinct substrate specificities, expression patterns, andmodes of regulation (Katso et al., 2001). The class I PI3Ks (p110α,p110β, p110δ, and p110γ) are typically activated by tyrosine kinases orG-protein coupled receptors to generate PIP3, which engages downstreameffectors such as those in the Akt/PDK1 pathway, mTOR, the Tec familykinases, and the Rho family GTPases. The class II and III PI3-Ks play akey role in intracellular trafficking through the synthesis of PI(3)Pand PI(3,4)P2. The PIKKs are protein kinases that control cell growth(mTORC1) or monitor genomic integrity (ATM, ATR, DNA-PK, and hSmg-1).

The delta (δ) isoform of class I PI3K has been implicated, inparticular, in a number of diseases and biological processes. PI3K δ isexpressed primarily in hematopoietic cells including leukocytes such asT-cells, dendritic cells, neutrophils, mast cells, B-cells, andmacrophages. PI3K δ is integrally involved in mammalian immune systemfunctions such as T-cell function, B-cell activation, mast cellactivation, dendritic cell function, and neutrophil activity. Due to itsintegral role in immune system function, P13K δ is also involved in anumber of diseases related to undesirable immune response such asallergic reactions, inflammatory diseases, inflammation mediatedangiogenesis, rheumatoid arthritis, auto-immune diseases such as lupus,asthma, emphysema and other respiratory diseases. Other class I PI3Kinvolved in immune system function includes PI3K γ, which plays a rolein leukocyte signaling and has been implicated in inflammation,rheumatoid arthritis, and autoimmune diseases such as lupus.

Downstream mediators of the PI3K signal transduction pathway include Aktand mammalian target of rapamycin (mTOR). Akt possesses a plckstrinhomology (PH) domain that binds PIP3, leading to Akt kinase activation.Akt phosphorylates many substrates and is a central downstream effectorof PI3K for diverse cellular responses. One important function of Akt isto augment the activity of mTOR, through phosphorylation of TSC2 andother mechanisms. mTOR is a serine-threonine kinase related to the lipidkinases of the PI3K family. mTOR has been implicated in a wide range ofbiological processes including cell growth, cell proliferation, cellmotility and survival. Disregulation of the mTOR pathway has beenreported in various types of cancer. mTOR is a multifunctional kinasethat integrates growth factor and nutrient signals to regulate proteintranslation, nutrient uptake, autophagy, and mitochondrial function.

As such, kinases, particularly PI3Ks are prime targets for drugdevelopment. There remains a need for PI3K inhibitors suitable for drugdevelopment. The present invention addresses this need and providesrelated advantages as well by providing new classes of kinaseinhibitors.

SUMMARY OF THE INVENTION

The present invention provides a compound having a structure of one ofthe following formulae:

or a pharmaceutically acceptable salt thereof, wherein:

X₅ and X₆ are C—R⁶, N, C-L¹-R¹, or N-L¹-R¹ wherein one of X₅ and X₆ isC-L¹-R¹ or N-L¹-R¹; X₁ is C or N; and X₂ and X₈ are independently N orC—R⁶; X₃ and X₇ are C or N, and at least one of X₃ and X₇ is C;

X₄ in Formula I-A or I-C is C or N; and X₄ in Formula I-B or I-D isC—R⁶, NH, or N;

and wherein no more than two adjacent ring atoms are N or NH;

R¹ is hydrogen, halogen, —CN, —OR¹⁰, —S(O)_(n)R¹¹, —NR¹²R¹³, —C(O)R¹⁴,alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,aryl, or heteroaryl, and n is an integer from 0 to 2;

L¹ is a bond, alkylene, heteroalkylene, alkenylene, alkynylene,cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

R² and R³ are independently hydrogen, halogen, —CN, —OR¹⁰, —S(O)_(n)R¹¹,—NR¹²R¹³, —C(O)R¹⁴, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,aryl, or heteroaryl;

R⁴ and R⁵ are independently hydrogen or R⁶, or R⁴ and R⁵ are takentogether to form a 5, 6 or 7 membered ring, wherein the 5, 6, or 7membered ring is optionally substituted with (R⁶)_(q);

L is —NH—CR⁷R⁸—, —(CR⁷R⁸)_(z)—, —C═O—, or —CR⁷R⁸(C═O)—, —O—, —SO—, or—SO₂—;

z is an integer from 0 to 10;

q is an integer from 0 to 5;

each of R⁶ is independently hydrogen, halogen, —CN, —OR¹⁰, —S(O)_(n)R¹¹,—NR¹²R¹³, —C(O)R¹⁴, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each of R⁷ and R⁸ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocyclyalkyl, or R⁷ and R⁸ taken together form acycloalkyl, heterocycloalkyl or aryl ring;

R⁹ is hydrogen, halogen, —CN, —OR¹⁰, —S(O)_(n)R¹¹, —NR¹²R¹³, —C(O)R¹⁴,alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,aryl, or heteroaryl;

each R¹⁰ is independently hydrogen, —C(O)R¹⁵, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R¹¹ is independently —NR¹⁶R¹⁷, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each R¹² is independently hydrogen, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each R¹³ is independently hydrogen, —S(O)_(n)R¹⁸, —C(O)R¹⁹, alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or R¹² and R¹³ are taken together to form a 5, 6, 7, or 8 membered ring,wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ringheteroatoms selected from N, S, or O in addition to the nitrogen atom of—NR¹²R¹³; and further wherein the 5, 6, 7, or 8 membered ring isoptionally substituted;

each R¹⁴ is independently —NR²⁰R²¹, hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R¹⁵ is independently —NR²²R²³, hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each of R⁶ and R¹⁷ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R¹⁶ and R¹⁷ aretaken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6,7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selectedfrom N, S, or O in addition to the nitrogen atom of —NR¹⁶R¹⁷; andfurther wherein the 5, 6, 7, or 8 membered ring is optionallysubstituted;

each R¹⁸ is independently hydrogen, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each R¹⁹ is independently —NR²⁴R²⁵, hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each of R²⁰ and R²¹ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or R²⁰ and R²¹ are taken together to form a 5, 6, 7, or 8 membered ring,wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ringheteroatoms selected from N, S, or O in addition to the nitrogen atom of—NR²⁰R²¹; and further wherein the 5, 6, 7, or 8 membered ring isoptionally substituted;

each R²² and R²³ are independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R²² and R²³ aretaken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6,7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selectedfrom N, S, or O in addition to the nitrogen atom of —NR²²R²³; andfurther wherein the 5, 6, 7, or 8 membered ring is optionallysubstituted;

each R²⁴ and R²⁵ are independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R²⁴ and R²⁵ aretaken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6,7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selectedfrom N, S, or O in addition to the nitrogen atom of —NR²⁴R²⁵; andfurther wherein the 5, 6, 7, or 8 membered ring is optionallysubstituted; and

W is CR⁶ or N.

In some embodiments, the compound of Formula I-A or I-C is a compoundhaving a structure of one of the following formulae:

In some embodiments, the compound of Formula I-E is a compound ofFormula I-J or Formula I-J-1:

In some embodiments, the compound of Formula I-A is a compound having astructure of one of the following formulae:

In some embodiments, the compound of Formula I-B or I-D, having astructure of one of the following formulae:

In another aspect, the invention provides for a compound having is acompound having a structure of the formula

or a pharmaceutically acceptable salt thereof, wherein:

X₅ and X₆ are C—R⁶, N, C-L¹-R¹, or N-L¹-R¹ wherein one and no more thanone of X₅ and X₆ is C-L¹-R¹ or N-L¹-R¹; X₁ is C or N; and X₂ and X₅ areindependently N, or C—R⁶; X₃ and X₇ are C or N, at least one of X₃ andX₇ is C;

X₄ in Formula V-A and Formula V-C is C or N; and X₄ in Formula V-B andFormula V-D is C—R⁶, NH, or N;

and wherein no more than two adjacent ring atoms are N or NH;

R¹ is hydrogen, halogen, —CN, —OR¹⁰, —S(O)_(n)R¹¹, —NR¹²R¹³, —C(O)R¹⁴,alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,aryl, or heteroaryl, and n is an integer from 0 to 2;

L¹ is a bond, alkylene, heteroalkylene, alkenylene, alkynylene,cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

each of R² and R³ is independently hydrogen, halogen, —CN, —OR¹⁰,—S(O)_(n)R¹¹, —NR¹²R¹³, —C(O)R¹⁴, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each of R⁴ and R⁵ is independently hydrogen or R⁶, or R⁴ and R⁵ aretaken together to form a 5, 6 or 7 membered ring, wherein the 5, 6, or 7membered ring is optionally substituted with (R⁶)_(q);

L is —NH—CR⁷R⁸—, —(CR⁷R⁸)_(z)—, —C═O—, or —CR⁷R⁸(C═O)—, —O—, —SO—, or—SO₂—;

z is an integer from 0 to 10;

q is an integer from 0 to 5;

each R⁶ is independently hydrogen, halogen, —CN, —OR¹⁰, —S(O)_(n)R¹¹,—NR¹²R¹³, —C(O)R¹⁴, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl, wherein n is independently aninteger from 0 to 2;

each of R⁷ and R⁸ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocyclyalkyl, or R⁷ and R⁸ taken together form acycloalkyl, heterocycloalkyl or aryl ring;

R⁹ is hydrogen, —C(O)R¹⁴, alkyl, alkenyl, alkynyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R¹⁰ is independently hydrogen, —C(O)R¹⁵, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R¹⁰ is independently —NR¹⁶R¹⁷, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each R¹² is independently hydrogen, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each R¹³ is independently hydrogen, —S(O)_(n)R¹⁸, —C(O)R¹⁹, alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or R¹² and R¹³ are taken together to form a 5, 6, 7, or 8 membered ring,wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ringheteroatoms selected from N, S, or O in addition to the nitrogen atom of—NR¹²R¹³, and further wherein the 5, 6, 7, or 8 membered ring isoptionally substituted;

each R¹⁴ is independently —NR²⁰R²¹, hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R¹⁵ is independently —NR²²R²³, hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each of R¹⁶ and R¹⁷ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R¹⁶ and R¹⁷ aretaken together to form a 5, 6, 7 or 8 membered ring, wherein the 5, 6,7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selectedfrom N, S, or O in addition to the nitrogen atom of —NR¹⁶R¹⁷, andfurther wherein the 5, 6, 7, or 8 membered ring is optionallysubstituted;

each R¹⁸ is independently hydrogen, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each R¹⁹ is independently —NR²⁴R²⁵, hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each of R²⁰ and R²¹ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R²⁰ and R²¹ aretaken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6,7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selectedfrom N, S, or O in addition to the nitrogen atom of —NR²⁰R²¹, andfurther wherein the 5, 6, 7, or 8 membered ring is optionallysubstituted;

each of R²² and R²³ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R²² and R²³ aretaken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6,7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selectedfrom N, S, or O in addition to the nitrogen atom of —NR²²R²³, andfurther wherein the 5, 6, 7, or 8 membered ring is optionallysubstituted; and

each of R²⁴ and R²⁵ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R²⁴ and R²⁵ aretaken together to form a 5, 6, 7, or 8 membered ring wherein the 5, 6,7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selectedfrom N, S, or O in addition to the nitrogen atom of —NR²⁴R²⁵, andfurther wherein the 5, 6, 7, or 8 membered ring is optionallysubstituted.

In some embodiments, the compound of Formula V-A is a compound having astructure of Formula VI-A1:

In another aspect, the invention provides for a compound having astructure of one of the following formulae

or a pharmaceutically acceptable salt thereof, wherein:

X₅ and X₆ are C—R⁶, N, C-L¹-R¹, or N-L¹-R¹ wherein one and no more thanone of X₅ and X₆ is C-L¹-R¹ or N-L¹-R¹;

X₁ is C or N; and X₂ and X₈ are independently N, or C—R⁶;

X₃ and X₇ are C or N, at least one of X₃ and X₇ is C;

X₄ in Formula VII-A and Formula VII-C is C or N; and X₄ in Formula VII-Band Formula VII-D is C—R⁶, NH, or N; and wherein no more than twoadjacent ring atoms are N or NH;

R¹ is hydrogen, halogen, —CN, —OR¹⁰, —S(O)_(n)R¹¹, —NR¹²R¹³, —C(O)R¹⁴,alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,aryl, or heteroaryl, and n is an integer from 0 to 2;

L¹ is a bond, alkylene, heteroalkylene, alkenylene, alkynylene,cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

each of R² and R³ is independently hydrogen, halogen, —CN, —OR¹⁰,—S(O)_(n)R¹¹, —NR¹²R¹³, —C(O)R¹⁴, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each of R⁴ and R⁵ is independently hydrogen or R⁶, or R⁴ and R⁵ aretaken together to form a 5, 6 or 7 membered ring, wherein the 5, 6, 7,or 8 membered ring is optionally substituted with (R⁶)_(q);

L is —NH—CR⁷R⁸—, —(CR⁷R⁸)_, —C═O—, or —CR⁷R⁸(C═O)—, —O—, —SO—, or —SO₂—;

z is an integer from 0 to 10;

q is an integer from 0 to 5;

each R⁶ is independently hydrogen, halogen, —CN, —OR¹⁰, —S(O)_(n)R¹¹,—NR¹²R¹³, —C(O)R¹⁴, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl, wherein n is independently aninteger from 0 to 2;

each of R⁷ and R⁸ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocyclyalkyl, or R⁷ and R⁸ taken together form acycloalkyl, heterocycloalkyl or aryl ring;

R⁹ is hydrogen, —C(O)R¹⁴, alkyl, alkenyl, alkynyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R¹⁰ is independently hydrogen, —C(O)R¹⁵, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R¹¹ is independently —NR¹⁶R¹⁷, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each R¹² is independently hydrogen, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each R¹³ is independently hydrogen, —S(O)_(n)R¹⁸, —C(O)R¹⁹, alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or R¹² and R¹³ are taken together to form a 5, 6, 7, or 8 membered ring,wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ringheteroatoms selected from N, S, or O in addition to the nitrogen atom of—NR¹²R¹³, and further wherein the 5, 6, 7, or 8 membered ring isoptionally substituted;

each R¹⁴ is independently —NR²⁰R²¹, hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R¹⁵ is independently —NR²²R²³, hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each of R¹⁶ and R¹⁷ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R¹⁶ and R¹⁷ aretaken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6,7, or 8 membered ring contains 0, 1, 2 or 3 additional ring heteroatomsselected from N, S, or O in addition to the nitrogen atom of —NR¹⁶R¹⁷,and further wherein the 5, 6, 7, or 8 membered ring is optionallysubstituted;

each R¹⁸ is independently hydrogen, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each R¹⁹ is independently —NR²⁴R²⁵, hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each of R²⁰ and R²¹ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R²⁰ and R²¹ aretaken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6,7, or 8 membered ring contains 0, 1, 2 or 3 additional ring heteroatomsselected from N, S, or O in addition to the nitrogen atom of —NR²⁰R²¹,and further wherein the 5, 6, 7, or 8 membered ring is optionallysubstituted;

each of R²² and R²³ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R²² and R²³ aretaken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6,7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selectedfrom N, S, or O in addition to the nitrogen atom of —NR²²R²³, andfurther wherein the 5, 6, 7, or 8 membered ring is optionallysubstituted; and

each of R²⁴ and R²⁵ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R²⁴ and R²⁵ aretaken together to form a 5, 6, 7, or 8 membered ring wherein the 5, 6,7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selectedfrom N, S, or O in addition to the nitrogen atom of —NR²⁴R²⁵, whereinthe 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 additional ringheteroatoms selected from N, S, or O, and further wherein the 5, 6, 7,or 8 membered ring is optionally substituted.

In some embodiments, compound of Formula VII-A is a compound having astructure of Formula VII-A1:

In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E,I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A,V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A,VII-A1, VII-A2, VII-B, VII-C, or VII-D, when L is —(CR⁷R⁸)_(z)- and z is1, then R¹ is alkynyl, aryl, or heteroaryl. In some other embodiments,when L is —(CR⁷R⁸)_(z)- and z is 1, then L¹ is a bond, and R¹ isalkynyl, aryl, or heteroaryl.

In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E,I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A,V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A,VII-A1, VII-A2, VII-B, VII-C, or VII-D, R⁹ is —OR¹⁰, —NR¹²R¹³, —C(O)R¹⁴,alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,aryl, or heteroaryl. In some embodiments, when R⁹ is aryl, then R⁹ issubstituted with halogen, alkyl or heteroalkyl. In other embodiments,wherein when R⁹ is —NR¹²R¹³, then R¹² and R¹³ are taken together to forma 5, 6, 7 or 8 membered ring.

In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E,I-F, I-G, I-H, I-J, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1,V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1,VII-A2, VII-B, VII-C, or VII-D, R¹ is bicyclic heteroaryl.

In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E,I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, V-A, V-A1, V-B, V-C,V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B,VII-C, or VII-D, R⁴ and R⁵ are taken together to form a 6-membered ring.

In some embodiments of a compound of Formula I-A, I-C, I-E, I-G, I-J,I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-C, VI-A,VI-A1, VI-A2, VI-C, VII-A, VII-A1, VII-A2, or VII-C, R² is —NH₂.

In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E,I-F, I-G, I-H, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-B, V-C, V-D,VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B,VII-C, or VII-D, R⁷ is alkyl.

In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E,I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A,V-A1, V-B, V-C, V-D, VI-A, VI-B, VI-C, VI-D, VII-A, VII-B, VII-C, orVII-D, R⁷ and R⁸ are hydrogen.

In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E,I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A,V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, or VI-D, W is CH.

In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E,I-F, I-G, I-H, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VII-A, VII-B,VII-C, or VII-D, W is N.

In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E,I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A,V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A,VII-A1, VII-A2, VII-B, VII-C, or VII-D, R³ is hydrogen.

In some embodiments of the invention, a compound of Formula I-A, I-B,I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2,III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C,VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided, whereinR⁹ is halogen, —CN, —OR¹⁰, —S(O)_(n)R¹¹, —NR¹²R¹³, —C(O)R¹⁴, alkyl,alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl, and wherein n is independently an integer from 0 to 2. Insome embodiments of the invention a compound of Formula I-A, I-B, I-C,I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A,IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D,VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided, wherein R⁹ isunsubstituted heterocycloalkyl. In some embodiments of the invention acompound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1,I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A,VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, orVII-D is provided, wherein R⁹ is substituted heterocycloalkyl. In someembodiments of the invention a compound of Formula I-A, I-B, I-C, I-D,I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A,V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A,VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided, wherein R⁹ isunsubstituted aryl or substituted aryl. In some embodiments, R⁹ is arylsubstituted with halogen, aryl substituted with alkyl, or arylsubstituted with heteroalkyl. In some embodiments of the invention acompound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1,I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A,VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, orVII-D is provided, wherein R⁹ is —NR¹²R¹³. In some embodiments of theinvention a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H,I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C,V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B,VII-C, or VII-D is provided, wherein R¹² is —H and R¹³ is unsubstitutedalkyl or cycloalkyl. Alternatively, R¹² and R¹³ are unsubstituted alkylor cycloalkyl. In some embodiments of the invention a compound ofFormula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A,II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2,VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-DD isprovided, wherein L¹ is a bond.

In some embodiments of the invention a compound of Formula I-A, I-B,I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2,III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C,VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided, whereinR¹ is monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, or bicyclicheteroaryl. In some embodiments, R¹ is unsubstituted aryl, orsubstituted aryl. In some embodiments, R¹ is aryl substituted withhalogen or hydroxy. In other embodiments, R¹ is aryl substituted withhalogen and hydroxy. In yet other embodiments, R¹ is unsubstitutedheteroaryl or substituted heteroaryl.

Alternatively, R¹ is unsubstituted alkynyl or substituted alkynyl. Insome embodiments, R¹ is alkynyl substituted with hydroxy. In furtherembodiments, R¹ is halogen, —CN, —C(═O)R¹⁴, alkyl, or alkenyl.

In some embodiments of the invention a compound of Formula I-A, I-B,I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2,III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C,VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided whereinR⁴ and R⁵ taken together form a 6-membered ring. The 6-membered ring canbe substituted with R⁶. In some embodiments, R⁶ in a compound of FormulaI-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1,II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B,VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D, is alkyl. Insome embodiments of the invention a compound of Formula I-A, I-B, I-C,I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A,IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D,VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided wherein R² is—NR¹²R¹³. In some embodiments, R² in a compound of Formula I-A, I-B,I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2,III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C,VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D, is —NH₂. In someembodiments of the invention a compound of Formula I-A, I-B, I-C, I-D,I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A,V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A,VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided wherein R⁷ is alkyl.In some embodiments of the invention a compound of Formula I-A, I-B,I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2,III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C,VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided whereinR⁷ and R⁸ are hydrogen. In some embodiments of the invention a compoundof Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K,II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1,VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-Dis provided wherein W is CH. In some embodiments of the invention acompound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1,I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A,VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, orVII-D is provided wherein z is 1. In some embodiments of the invention acompound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1,I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A,VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, orVII-D is provided wherein R³ is hydrogen.

In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E,I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A,V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A,VII-A1, VII-A2, VII-B, VII-C, or VII-D, the compound selectivelyinhibits one or more members of type I phosphatidylinositol 3-kinases(PI3-kinase) relative to other members of type I PI3-kinase, ascertainedby an in vitro kinase assay. In some embodiments, the compoundselectively inhibits PI3-kinase γ and PI3-kinase δ as compared toPI3-kinase β and PI3-kinase α. In other embodiments, the compoundselectively inhibits PI3-kinase δ and PI3-kinase β as compared toPI3-kinase α and PI3-kinase γ.

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H,I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C,V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B,VII-C, VII-D or a pharmaceutically acceptable salt of a compound ofFormula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A,II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2,VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D, and apharmaceutically acceptable excipient.

The invention also provides a method of treating a medical conditionmediated by a type I-PI3 kinase (e.g. mediated by p110δ, p110γ, p110α,or p110β kinase), comprising administering to a subject in need thereofa therapeutically effective amount of a compound of Formula I-A, I-B,I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2,III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C,VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D, or apharmaceutically acceptable salt of a compound of Formula I-A, I-B, I-C,I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A,IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D,VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D. In some embodiments, themedical condition is selected from the group consisting of hematologicmalignancy, inflammation, autoimmune disease, rheumatoid arthritis,systemic lupus erythematosus, asthma, and cardiovascular disease. Inother embodiments, the medical condition is selected from the groupconsisting of acute myelogenous leukemia, chronic myelogenous leukemia,mastocytosis, chronic lymphocytic leukemia, multiple myeloma, andmyelodysplastic syndrome. In other embodiments, the method of treating amedical condition further comprises administering an anti-cancer agent.

The present invention also provides a method of inhibiting activity of aprotein kinase and/or a lipid kinase present in a cell, comprisingcontacting said cell with an effective amount of a compound of FormulaI-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1,II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B,VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D or apharmaceutically acceptable salt of a compound of Formula I-A, I-B, I-C,I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A,IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D,VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures wherein hydrogen is replaced by deuterium or tritium, orwherein carbon atom is replaced by ¹³C- or ¹⁴C-enriched carbon, arewithin the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of atoms that constitutesuch compounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe present invention, whether radioactive or not, are encompassedwithin the scope of the present invention.

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary from, for example, between 1% and 15% of the statednumber or numerical range. The term “comprising” (and related terms suchas “comprise” or “comprises” or “having” or “including”) includes thoseembodiments, for example, an embodiment of any composition of matter,composition, method, or process, or the like, that “consist of” or“consist essentially of” the described features.

As used in the specification and claims, the singular form “a”, “an” and“the” includes plural references unless the context clearly dictatesotherwise.

As used herein, “agent” or “biologically active agent” refers to abiological, pharmaceutical, or chemical compound or other moiety.Non-limiting examples include simple or complex organic or inorganicmolecule, a peptide, a protein, an oligonucleotide, an antibody, anantibody derivative, antibody fragment, a vitamin derivative, acarbohydrate, a toxin, or a chemotherapeutic compound. Various compoundscan be synthesized, for example, small molecules and oligomers (e.g.,oligopeptides and oligonucleotides), and synthetic organic compoundsbased on various core structures. In addition, various natural sourcescan provide compounds for screening, such as plant or animal extracts,and the like. A skilled artisan can readily recognize that there is nolimit as to the structural nature of the agents of the presentinvention.

The term “agonist” as used herein refers to a compound having theability to initiate or enhance a biological function of a targetprotein, whether by inhibiting the activity or expression of the targetprotein. Accordingly, the term “agonist” is defined in the context ofthe biological role of the target polypeptide. While preferred agonistsherein specifically interact with (e.g. bind to) the target, compoundsthat initiate or enhance a biological activity of the target polypeptideby interacting with other members of the signal transduction pathway ofwhich the target polypeptide is a member are also specifically includedwithin this definition.

The terms “antagonist” and “inhibitor” are used interchangeably, andthey refer to a compound having the ability to inhibit a biologicalfunction of a target protein, whether by inhibiting the activity orexpression of the target protein. Accordingly, the terms “antagonist”and “inhibitors” are defined in the context of the biological role ofthe target protein. While preferred antagonists herein specificallyinteract with (e.g. bind to) the target, compounds that inhibit abiological activity of the target protein by interacting with othermembers of the signal transduction pathway of which the target proteinis a member are also specifically included within this definition. Apreferred biological activity inhibited by an antagonist is associatedwith the development, growth, or spread of a tumor, or an undesiredimmune response as manifested in autoimmune disease.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.One class of anti-cancer agents comprises chemotherapeutic agents.“Chemotherapy” means the administration of one or more chemotherapeuticdrugs and/or other agents to a cancer patient by various methods,including intravenous, oral, intramuscular, intraperitoneal,intravesical, subcutaneous, transdermal, buccal, or inhalation or in theform of a suppository.

The term “cell proliferation” refers to a phenomenon by which the cellnumber has changed as a result of division. This term also encompassescell growth by which the cell morphology has changed (e.g., increased insize) consistent with a proliferative signal.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound described herein that is sufficient toeffect the intended application including but not limited to diseasetreatment, as defined below. The therapeutically effective amount mayvary depending upon the intended application (in vitro or in vivo), orthe subject and disease condition being treated, e.g., the weight andage of the subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g. reduction of plateletadhesion and/or cell migration. The specific dose will vary depending onthe particular compounds chosen, the dosing regimen to be followed,whether it is administered in combination with other compounds, timingof administration, the tissue to which it is administered, and thephysical delivery system in which it is carried.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” is used interchangeably herein. These terms refer to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. Bytherapeutic benefit is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forprophylactic benefit, the compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

The term “pharmaceutically acceptable salt” refers to salts derived froma variety of organic and inorganic counter ions well known in the art.Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids. Inorganic acids from which salts canbe derived include, for example, hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acidsfrom which salts can be derived include, for example, acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and thelike. Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc,copper, manganese, aluminum, and the like. Organic bases from whichsalts can be derived include, for example, primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, basic ion exchange resins, and thelike, specifically such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, and ethanolamine. In some embodiments,the pharmaceutically acceptable base addition salt is chosen fromammonium, potassium, sodium, calcium, and magnesium salts.

“Pharmaceutically acceptable carrier” or “pharmaceutically acceptableexcipient” includes any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions of theinvention is contemplated. Supplementary active ingredients can also beincorporated into the compositions.

“Signal transduction” is a process during which stimulatory orinhibitory signals are transmitted into and within a cell to elicit anintracellular response. A modulator of a signal transduction pathwayrefers to a compound which modulates the activity of one or morecellular proteins mapped to the same specific signal transductionpathway. A modulator may augment (agonist) or suppress (antagonist) theactivity of a signaling molecule.

“Radiation therapy” means exposing a patient, using routine methods andcompositions known to the practitioner, to radiation emitters such asalpha-particle emitting radionucleotides (e.g., actinium and thoriumradionuclides), low linear energy transfer (LET) radiation emitters(i.e. beta emitters), conversion electron emitters (e.g. strontium-89and samarium-153-EDTMP, or high-energy radiation, including withoutlimitation x-rays, gamma rays, and neutrons.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers advantages of solubility,tissue compatibility or delayed release in a mammalian organism (see,e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al.,“Pro-drugs as Novel Delivery Systems,” A.C.S.

Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design,ed. Edward B. Roche, American Pharmaceutical Association and PergamonPress, 1987, both of which are incorporated in full by reference herein.The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of an active compound, asdescribed herein, may be prepared by modifying functional groups presentin the active compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent activecompound. Prodrugs include compounds wherein a hydroxy, amino ormercapto group is bonded to any group that, when the prodrug of theactive compound is administered to a mammalian subject, cleaves to forma free hydroxy, free amino or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, acetate, formateand benzoate derivatives of an alcohol or acetamide, formamide andbenzamide derivatives of an amine functional group in the activecompound and the like.

“Acyl” refers to a —(C═O)R radical wherein “R” is alkyl, aryl,heteroaryl, heteroalkyl, or heterocyclyl, which are as described herein.In some embodiments, it is a C₁-C₁₀ acyl radical which refers to thetotal number of chain or ring atoms of the alkyl, aryl, heteroaryl orheterocyclyl portion of the acyloxy group plus the carbonyl carbon ofacyl, i.e three other ring or chain atoms plus carbonyl. If the Rradical is heteroaryl or heterocyclyl, the hetero ring or chain atomscontribute to the total number of chain or ring atoms. Unless statedotherwise specifically in the specification, the “R” of an acyloxy groupis optionally substituted by one or more substituents whichindependently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or PO₃(R^(a))₂, whereeach R^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl. “Acyloxy” refers to a R(C═O)O— radicalwherein “R” is alkyl, aryl, heteroaryl or heterocyclyl, which are asdescribed herein. In some embodiments, it is a C₁-C₄ acyloxy radicalwhich refers to the total number of chain or ring atoms of the alkyl,aryl, heteroaryl or heterocyclyl portion of the acyloxy group plus thecarbonyl carbon of acyl, i.e three other ring or chain atoms pluscarbonyl. If the R radical is heteroaryl or heterocyclyl, the heteroring or chain atoms contribute to the total number of chain or ringatoms. Unless stated otherwise specifically in the specification, the“R” of an acyloxy group is optionally substituted by one or more of thefollowing substituents: alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R⁸, —N(R^(a))₂, —C(O)R⁸,—C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2) —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), —OPO₃WY (where W and Yare hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or—OPO₃Z (where Z is calcium, magnesium or iron) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Aralkyl” or “arylalkyl” refers to an (aryl)alkyl-radical where aryl andalkyl are as disclosed herein and which are optionally substituted byone or more of the subsituents described as suitable substituents foraryl and alkyl respectively.

“Alkoxy” refers to a (alkyl)O-radical, where alkyl is as describedherein and contains 1 to 10 carbons (e.g., C₁-C₁₀ alkyl). Whenever itappears herein, a numerical range such as “1 to 10” refers to eachinteger in the given range; e.g., “1 to 10 carbon atoms” means that thealkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbonatoms, etc., up to and including 10 carbon atoms. In some embodiments,it is a C₁-C₄ alkoxy group. A alkoxy moiety may be substituted by one ormore of the substituents described as suitable substituents for an alkylradical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to ten carbon atoms (e.g., C₁-C₁₀ alkyl).Whenever it appears herein, a numerical range such as “1 to 10” refersto each integer in the given range; e.g., “1 to 10 carbon atoms” meansthat the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 10 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated. In some embodiments, it is a C₁-C₄alkyl group. Typical alkyl groups include, but are in no way limited to,methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butylisobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl,octyl, nonyl, decyl, and the like. The alkyl is attached to the rest ofthe molecule by a single bond, for example, methyl (Me), ethyl (Et),n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.Unless stated otherwise specifically in the specification, an alkylgroup is optionally substituted by one or more of the followingsubstituents: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where tis 1 or 2), —S(O)OR^(a) (where t is 1 or 2) —S(O)_(t)N(R^(a))₂ (where tis 1 or 2), —OPO₃WY (where W and Y are hydrogen, methyl, ethyl, alkyl,lithium, sodium or potassium) or —OPO₃Z (where Z is calcium, magnesiumor iron) where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

An “alkene” moiety refers to a group consisting of at least two carbonatoms and at least one carbon-carbon double bond, and an “alkyne” moietyrefers to a group consisting of at least two carbon atoms and at leastone carbon-carbon triple bond. The alkyl moiety, whether saturated orunsaturated, may be branched, straight chain, or cyclic.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, and having from two to ten carbon atoms (ie.C₂-C₁₀ alkenyl). Whenever it appears herein, a numerical range such as“2 to 10” refers to each integer in the given range; e.g., “2 to 10carbon atoms” means that the alkenyl group may consist of 2 carbonatoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. Incertain embodiments, an alkenyl comprises two to eight carbon atoms. Inother embodiments, an alkenyl comprises two to five carbon atoms (e.g.,C₂-C₅ alkenyl). The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more of the following substituentsalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,nitro, oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R⁸)C(O)OR⁸,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2) —S(O)_(t)N(R^(a))₂ (where t is 1 or2), —OPO₃WY (where W and Y are hydrogen, methyl, ethyl, alkyl, lithium,sodium or potassium) or —OPO₃Z (where Z is calcium, magnesium or iron)where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having from two to ten carbon atoms (ie.C₂-C_(1l) alkynyl). Whenever it appears herein, a numerical range suchas “2 to 10” refers to each integer in the given range; e.g., “2 to 10carbon atoms” means that the alkynyl group may consist of 2 carbonatoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. Incertain embodiments, an alkynyl comprises two to eight carbon atoms. Inother embodiments, an alkynyl has two to five carbon atoms (e.g., C₂-C₅alkynyl). The alkynyl is attached to the rest of the molecule by asingle bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl,and the like.

Unless stated otherwise specifically in the specification, an alkynylgroup is optionally substituted by one or more of the followingsubstituents alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where tis 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2) —S(O)_(t)N(R^(a))₂(where t is 1 or 2), —OPO₃WY (where W and Y are hydrogen, methyl, ethyl,alkyl, lithium, sodium or potassium) or —OPO₃Z (where Z is calcium,magnesium or iron) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Amino” or “amine” refers to a —N(R^(a))₂ radical group, where eachR^(a) is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl, unless stated otherwise specifically inthe specification. Unless stated otherwise specifically in thespecification, an amino group is optionally substituted by one or moresubstituents which independently are: alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(n)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2) —S(O)_(t)N(R^(a))₂ (where t is 1 or2), —OPO₃WY (where W and Y are hydrogen, methyl, ethyl, alkyl, lithium,sodium or potassium) or —OPO₃Z (where Z is calcium, magnesium or iron)where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Amide” or “amido” refers to a chemical moiety with formula —C(O)NHR or—NHC(O)R, where R is selected from the group consisting of alkyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon). In some embodiments itis a C₁-C₄ amido or amide radical, which includes the amide carbonyl inthe total number of carbons in the radical. Unless stated otherwisespecifically in the specification, an amino group is optionallysubstituted independently by one or more of the substituents asdescribed herein for alkyl, cycloalkyl, aryl, heteroaryl, orheterocyclyl. An amide may be an amino acid or a peptide moleculeattached to a compound of Formula (I), thereby forming a prodrug. Anyamine, hydroxy, or carboxyl side chain on the compounds described hereincan be amidified. The procedures and specific groups to make such amidesare known to those of skill in the art and can readily be found inreference sources such as Greene and Wuts, Protective Groups in OrganicSynthesis, 3.sup.rd Ed., John Wiley & Sons, New York, N.Y., 1999, whichis incorporated herein by reference in its entirety.

“Aromatic” or “aryl” refers to an aromatic radical with six to ten ringatoms (e.g., C₆-C₁₀ aromatic or C₆-C₁₀ aryl) which has at least one ringhaving a conjugated pi electron system which is carbocyclic (e.g.,phenyl, fluorenyl, and naphthyl). Whenever it appears herein, anumerical range such as “6 to 10” refers to each integer in the givenrange; e.g., “6 to 10 ring atoms” means that the aryl group may consistof 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms.The term includes monocyclic or fused-ring polycyclic (i.e., rings whichshare adjacent pairs of ring atoms) groups. Unless stated otherwisespecifically in the specification, an aryl moiety is optionallysubstituted by one or more substituents which are independently: alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro,oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where tis 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2) —S(O)_(t)N(R^(a))₂(where t is 1 or 2), —OPO₃WY (where W and Y are hydrogen, methyl, ethyl,alkyl, lithium, sodium or potassium) or —OPO₃Z (where Z is calcium,magnesium or iron) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Carboxaldehyde” refers to a —(C═O)H radical.

“Carboxyl” refers to a —(C═O)OH radical.

“Cyano” refers to a —CN radical.

“Cycloalkyl” refers to a monocyclic or polycyclic radical that containsonly carbon and hydrogen, and may be saturated, or partiallyunsaturated. Cycloalkyl groups include groups having from 3 to 10 ringatoms (ie. C₂-C₁₀ cycloalkyl). Whenever it appears herein, a numericalrange such as “3 to 10” refers to each integer in the given range; e.g.,“3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3carbon atoms, etc., up to and including 10 carbon atoms. In someembodiments, it is a C₃-C₅ cycloalkyl radical. Illustrative examples ofcycloalkyl groups include, but are not limited to the followingmoieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloseptyl,cyclooctyl, cyclononyl, cyclodecyl, norbomyl, and the like. Unlessstated otherwise specifically in the specification, a cycloalkyl groupis optionally substituted by one or more substituents whichindependently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where tis 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2) —S(O)_(t)N(R^(a))₂(where t is 1 or 2), —OPO₃WY (where W and Y are hydrogen, methyl, ethyl,alkyl, lithium, sodium or potassium) or —OPO₃Z (where Z is calcium,magnesium or iron) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Ester” refers to a chemical radical of formula —COOR, where R isselected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and heteroalicyclic (bondedthrough a ring carbon). Any amine, hydroxy, or carboxyl side chain onthe compounds described herein can be esterified. The procedures andspecific groups to make such esters are known to those of skill in theart and can readily be found in reference sources such as Greene andWuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley &Sons, New York, N.Y., 1999, which is incorporated herein by reference inits entirety. Unless stated otherwise specifically in the specification,an ester group is optionally substituted by one or more substituentswhich independently are: alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R⁸, —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2) —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), —OPO₃WY (where W and Yare hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or—OPO₃Z (where Z is calcium, magnesium or iron) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of thefluoroalkyl radical may be optionally substituted as defined above foran alkyl group.

“Halo”, “halide”, or, alternatively, “halogen” means fluoro, chloro,bromo or iodo. The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and“haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures thatare substituted with one or more halo groups or with combinationsthereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” includehaloalkyl and haloalkoxy groups, respectively, in which the halo isfluorine.

“Heteroalkyl” “heteroalkenyl” and “heteroalkynyl” include optionallysubstituted alkyl, alkenyl and alkynyl radicals and which have one ormore skeletal chain atoms selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Anumerical range may be given, e.g. C₁-C₄ heteroalkyl which refers to thechain length in total, which in this example is 4 atoms long. Forexample, a —CH₂OCH₂CH₃ radical is referred to as a “C₄” heteroalkyl,which includes the heteroatom center in the atom chain lengthdescription. Connection to the rest of the molecule may be througheither a heteroatom or a carbon in the heteroalkyl chain. A heteroalkylgroup may be substituted with one or more substituents whichindependently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy,halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where tis 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2) —S(O)_(t)N(R^(a))₂(where t is 1 or 2), —OPO₃WY (where W and Y are hydrogen, methyl, ethyl,alkyl, lithium, sodium or potassium) or —OPO₃Z (where Z is calcium,magnesium or iron) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Heteroaryl” or, alternatively, “heteroaromatic” refers to a 5- to18-membered aromatic radical (e.g., C₅-C₁₃ heteroaryl) that includes oneor more ring heteroatoms selected from nitrogen, oxygen and sulfur, andwhich may be a monocyclic, bicyclic, tricyclic or tetracyclic ringsystem. Whenever it appears herein, a numerical range such as “5 to 18”refers to each integer in the given range; e.g., “5 to 18 ring atoms”means that the heteroaryl group may consist of 5 ring atoms, 6 ringatoms, etc., up to and including 18 ring atoms. An N-containing“heteroaromatic” or “heteroaryl” moiety refers to an aromatic group inwhich at least one of the skeletal atoms of the ring is a nitrogen atom.The polycyclic heteroaryl group may be fused or non-fused. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, aheteraryl moiety is optionally substituted by one or more substituentswhich are independently: alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2) —S(O)_(t)N(R^(a))₂ (where t is 1 or2), —OPO₃WY (where W and Y are hydrogen, methyl, ethyl, alkyl, lithium,sodium or potassium) or —OPO₃Z (where Z is calcium, magnesium or iron)where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Heteroarylalkyl” or “hetarylalkyl” refers to an(heteroaryl)alkyl-radical where heteroaryl and alkyl are as disclosedherein and which are optionally substituted by one or more of thesubstituents described as suitable substituents for aryl and alkylrespectively.

“Heterocyclyl” or “heterocycloalkyl” refers to a stable 3- to18-membered non-aromatic ring (e.g., C₃-C₁₈ heterocyclyl) radical thatcomprises two to twelve carbon atoms and from one to six heteroatomsselected from nitrogen, oxygen and sulfur. Whenever it appears herein, anumerical range such as “3 to 18” refers to each integer in the givenrange; e.g., “3 to 18 ring atoms” means that the heteroaryl group mayconsist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ringatoms. In some embodiments, it is a C₅-C₁₀ heterocyclyl. In someembodiments, it is a C₄-C₁₀ heterocyclyl. In some embodiments, it is aC₃-C₁₀ heterocyclyl. Unless stated otherwise specifically in thespecification, the heterocyclyl radical is a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include fused or bridgedring systems. The heteroatoms in the heterocyclyl radical may beoptionally oxidized. One or more nitrogen atoms, if present, areoptionally quaternized. The heterocyclyl radical is partially or fullysaturated. The heterocyclyl may be attached to the rest of the moleculethrough any atom of the ring(s). Examples of such heterocyclyl radicalsinclude, but are not limited to 6,7-dihydro-5H-cyclopenta[b]pyridine,dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, a heterocylyl moiety is optionally substituted by one ormore substituents which independently are: alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2) —S(O)_(t)N(R^(a))₂ (where t is 1 or2), —OPO₃WY (where W and Y are hydrogen, methyl, ethyl, alkyl, lithium,sodium or potassium) or —OPO₃Z (where Z is calcium, magnesium or iron)where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Heteroalicyclic” refers to a cycloalkyl radical that includes at leastone heteroatom selected from nitrogen, oxygen and sulfur. The radicalsmay be fused with an aryl or heteroaryl. The term heteroalicyclic alsoincludes all ring forms of the carbohydrates, including but not limitedto the monosaccharides, the disaccharides and the oligosaccharides.Unless stated otherwise specifically in the specification, aheteroalicyclic group is optionally substituted by one or more ofsubstituents which are independently: alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))S(O)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2) —S(O)_(t)N(R^(a))₂ (where t is 1 or2), —OPO₃WY (where W and Y are hydrogen, methyl, ethyl, alkyl, lithium,sodium or potassium) or —OPO₃Z (where Z is calcium, magnesium or iron)where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Imino” refers to the ═N—H radical.

“Isocyanato” refers to a —NCO radical.

“Isothiocyanato” refers to a —NCS radical.

“Mercaptyl” refers to a (alkyl)S— or (H)S— radical.

“Moiety” refers to a specific segment or functional group of a molecule.Chemical moieties are often recognized chemical entities embedded in orappended to a molecule.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Sulfininyl” refers to a —S(═O)—R radical, where R is selected from thegroup consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded througha ring carbon) and heteroalicyclic (bonded through a ring carbon).

“Sulfonyl” refers to a —S(═O)₂—R radical, where R is selected from thegroup consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded througha ring carbon) and heteroalicyclic (bonded through a ring carbon).

“Sulfonamidyl” or “sulfonamido” refers to a —S(═O)₂—NRR radical, whereeach R is selected independently from the group consisting of hydrogen,alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon). In some embodiments, itis a C₁-C₄ sulfonamido, wherein each R in sulfonamido contains 1 carbon,2 carbons, 3 carbons, or 4 carbons total. A sulfonamido group isoptionally substituted by one or more of the substituents described foralkyl, cycloalkyl, aryl, heteroaryl respectively

“Sulfoxyl” refers to a —S(═O)₂OH radical.

“Sulfonate” refers to a —S(═O)₂—OR radical, where R is selected from thegroup consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded througha ring carbon) and heteroalicyclic (bonded through a ring carbon). Asulfonate group is optionally substituted on R by one or more of thesubstituents described for alkyl, cycloalkyl, aryl, heteroarylrespectively.

“Thiocyanato” refers to a —CNS radical.

“Thioxo” refers to the ═S radical.

“Substituted” means that the referenced group may be substituted withone or more additional group(s) individually and independently selectedfrom acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate,heteroaryl, heterocyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio,arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato,thiocyanato, isothiocyanato, nitro, perhaloalkyl, perfluoroalkyl,phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate,and amino, including mono- and di-substituted amino groups, and theprotected derivatives thereof. The substituents themselves may besubstituted, for example, a cycloakyl substituent may have a halidesubstituted at one or more ring carbons, and the like. The protectinggroups that may form the protective derivatives of the abovesubstituents are known to those of skill in the art and may be found inreferences such as Greene and Wuts, above.

The compounds presented herein may possess one or more chiral centersand each center may exist in the R or S configuration. The compoundspresented herein include all diastereomeric, enantiomeric, and epimericforms as well as the appropriate mixtures thereof. Stereoisomers may beobtained, if desired, by methods known in the art as, for example, theseparation of stereoisomers by chiral chromatographic columns.

The methods and formulations described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), orpharmaceutically acceptable salts of compounds having the structure ofFormula (I), as well as active metabolites of these compounds having thesame type of activity. In addition, the compounds described herein canexist in unsolvated as well as solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. The solvatedforms of the compounds presented herein are also considered to bedisclosed herein.

The term “selective inhibition” or “selectively inhibit” as referred toa biologically active agent refers to the agent's ability topreferentially reduce the target signaling activity as compared tooff-target signaling activity, via direct or interact interaction withthe target.

Compounds described can contain one or more asymmetric centers and maythus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. All formulae disclosed here are shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of the shown formulae and pharmaceutically acceptablesalts thereof. Further, mixtures of stereoisomers as well as isolatedspecific stereoisomers are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

“Isomers” are different compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space, i.e. having a different stereochemical configuration.“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(.±.)” is used to designate a racemicmixture where appropriate. “Diastereoisomers” are stereoisomers thathave at least two asymmetric atoms, but which are not mirror-images ofeach other. The absolute stereochemistry is specified according to theCahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer thestereochemistry at each chiral carbon can be specified by either R or S.Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. Certain of the compounds described herein containone or more asymmetric centers and can thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that can be defined, interms of absolute stereochemistry, as (R)- or (S)-. The present chemicalentities, pharmaceutical compositions and methods are meant to includeall such possible isomers, including racemic mixtures, optically pureforms and intermediate mixtures. Optically active (R)- and (S)-isomerscan be prepared using chiral synthons or chiral reagents, or resolvedusing conventional techniques. When the compounds described hereincontain olefinic double bonds or other centers of geometric asymmetry,and unless specified otherwise, it is intended that the compoundsinclude both E and Z geometric isomers.

“Moiety” refers to a specific segment or functional group of a molecule.Chemical moieties are often recognized chemical entities embedded in orappended to a molecule.

A “leaving group or atom” is any group or atom that will, under thereaction conditions, cleave from the starting material, thus promotingreaction at a specified site. Suitable examples of such groups unlessotherwise specified are halogen atoms, mesyloxy,p-nitrobenzensulphonyloxy and tosyloxy groups.

“Protecting group” has the meaning conventionally associated with it inorganic synthesis, i.e. a group that selectively blocks one or morereactive sites in a multifunctional compound such that a chemicalreaction can be carried out selectively on another unprotected reactivesite and such that the group can readily be removed after the selectivereaction is complete. A variety of protecting groups are disclosed, forexample, in T. H. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, New York (1999). Forexample, a hydroxy protected form is where at least one of the hydroxygroups present in a compound is protected with a hydroxy protectinggroup. Likewise, amines and other reactive groups may similarly beprotected

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompass administrationof two or more agents to an animal so that both agents and/or theirmetabolites are present in the animal at the same time.Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

The term “in vivo” refers to an event that takes place in a subject'sbody.

The term “in vitro” refers to an event that takes places outside of asubject's body. For example, an in vitro assay encompasses any assay runoutside of a subject assay. In vitro assays encompass cell-based assaysin which cells alive or dead are employed. In vitro assays alsoencompass a cell-free assay in which no intact cells are employed.

A “subject,” “individual” or “patient” is used interchangeably herein,which refers to a vertebrate, preferably a mammal, more preferably ahuman. Mammals include, but are not limited to, murines, simians,humans, farm animals, sport animals, and pets. Tissues, cells and theirprogeny of a biological entity obtained in vitro or cultured in vitroare also encompassed.

II. Compositions

In one aspect, the present invention provides a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

X₅ and X₆ are C—R⁶, N, C-L¹-R¹, or N-L¹-R¹ wherein one of X₅ and X₆ isC-L¹-R¹ or N-L¹-R¹;

X₁ is C or N; and X₂ and X₈ are independently N or C-R⁶;

X₃ and X₇ are C or N, and at least one of X₃ and X₇ is C;

X₄ in Formula I-A or I-C is C or N; and X₄ in Formula I-B or I-D isC—R⁶, NH, or N; and no more than two adjacent ring atoms are N or NH;

R¹ is hydrogen, halogen, —CN, —OR¹⁰, —S(O)_(a)R¹¹, —NR¹²R¹³, —C(O)R¹⁴,alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,aryl, or heteroaryl, and n is an integer from 0 to 2;

L¹ is a bond, alkylene, heteroalkylene, alkenylene, alkynylene,cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

R² and R³ are independently hydrogen, halogen, —CN, —OR¹⁰, —S(O)_(n)R¹¹,—NR¹²R¹³, —C(O)R⁴, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,aryl, or heteroaryl;

R⁴ and R⁵ are independently hydrogen or R⁶, or R⁴ and R⁵ are takentogether to form a 5, 6 or 7-membered ring, wherein the 5, 6, or 7membered ring is optionally substituted with (R⁶)_(q);

L is —NH—CR⁷R⁸—, —(CR⁷R⁸)_(z)—, —C═O—, or —CR⁷R⁸(C═O)—, —O—, —SO—, or—SO₂—;

z is an integer from 0 to 10;

q is an integer from 0 to 5;

each of R⁶ is independently hydrogen, halogen, —CN, —OR¹⁰, —S(O)_(n)R¹¹,—NR²R³, —C(O)R⁴, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each of R⁷ and R⁸ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocyclyalkyl, or R⁷ and R⁸ taken together form acycloalkyl, heterocycloalkyl or aryl ring;

R⁹ is hydrogen, halogen, —CN, —OR¹⁰, —S(O)_(n)R¹¹, —NR¹²R¹³, —C(O)R¹⁴,alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,aryl, or heteroaryl;

each R¹⁰ is independently hydrogen, —C(O)R¹⁵, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R¹¹ is independently —NR¹⁶R¹⁷, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each R¹² is independently hydrogen, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each R¹³ is independently hydrogen, —S(O)_(n)R¹⁸, —C(O)R¹⁹, alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or R¹² and R¹³ are taken together to form a 5, 6 or 7-membered ring,wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ringheteroatoms selected from N, S, or O in addition to the nitrogen atom of—NR¹²R¹³; and further wherein the 5, 6, 7, or 8 membered ring isoptionally substituted;

each R¹⁴ is independently —NR²⁰ R²¹, hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R¹⁵ is independently —NR²²R²³, hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each of R⁶ and R¹⁷ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or R¹⁶ and R¹⁷ are taken together to form a 5, 6 or 7-membered ring,wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ringheteroatoms selected from N, S, or O in addition to the nitrogen atom of—NR¹⁶R¹⁷; and further wherein the 5, 6, 7, or 8 membered ring isoptionally substituted;

each R¹⁸ is independently hydrogen, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each R¹⁹ is independently —NR²⁴R²⁵, hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each of R²⁰ and R²¹ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R²⁰ and R²¹ aretaken together to form a 5, 6 or 7-membered ring, wherein the 5, 6, 7,or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected fromN, S, or O in addition to the nitrogen atom of —NR²⁰R²¹; and furtherwherein the 5, 6, 7, or 8 membered ring is optionally substituted;

each of R²² and R²³ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R²² and R²³ aretaken together to form a 5, 6 or 7-membered ring, wherein the 5, 6, 7,or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected fromN, S, or O in addition to the nitrogen atom of —NR²²R²³; and furtherwherein the 5, 6, 7, or 8 membered ring is optionally substituted;

each of R²⁴ and R²⁵ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R²⁴ and R²⁵ aretaken together to form a 5, 6 or 7-membered ring, wherein the 5, 6, 7,or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected fromN, S, or O in addition to the nitrogen atom of —NR²⁴R²⁵; and furtherwherein the 5, 6, 7, or 8 membered ring is optionally substituted; and

W is C—R⁶ or N.

In some embodiments, a compound of one of Formula I-A, I-B, I-C, or I-Dhas a structure of one of the following formulae:

In some embodiments of the invention, the compound of Formula I-E has astructure of Formula I-J or Formula I-K:

In some embodiments, the compound of Formulal-J is a compound of FormulaI-J-1:

In some embodiments, the compound of Formula I-E is a compound ofFormula II-A, Formula II-A1 or Formula II-A2:

In other embodiments, a compound of Formula I-E has a structure ofFormula III-A:

In other embodiments, a compound of Formula I-E has a structure ofFormula IV-A:

In some embodiments, W is C—R⁶. In other embodiments, W is CH. In yetother embodiments W is N.

In another aspect, a compound of the invention has a structure of one ofthe following formulae:

or a pharmaceutically acceptable salt thereof, wherein:

W is C—R⁶ or N;

X₅ and X₆ are C—R⁶, N, C-L¹-R¹, or N-L¹-R¹ wherein one and no more thanone of X₅ and X₆ is C-L¹-R¹ or N-L¹-R¹;

X₁ is C or N; and X₂ and X₈ are independently N, or C—R⁶;

X₃ and X₇ are C or N, at least one of X₃ and X₇ is C;

X₄ in Formula V-A and Formula V-C is C or N; and X₄ in Formula V-B andFormula V-D is C—R⁶, NH, or N; and wherein no more than two adjacentring atoms are N or NH;

R¹ is hydrogen, halogen, —CN, —OR¹⁰ , —S(O)_(n)R¹¹, —NR¹²R¹³, —C(O)R¹⁴,alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,aryl, or heteroaryl, and n is an integer from 0 to 2;

L¹ is a bond, alkylene, heteroalkylene, alkenylene, alkynylene,cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;

each of R² and R³ is independently hydrogen, halogen, —CN, —OR¹⁰,—S(O)_(n)R¹¹, —NR¹²R¹³, —C(O)R¹⁴, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each of R⁴ and R⁵ is independently hydrogen or R⁶, or R⁴ and R⁵ aretaken together to form a 5, 6 or 7 membered ring, wherein the 5, 6, or 7membered ring is optionally substituted with (R⁶)_(q);

L is —NH—CR⁷R⁸—, —(CR⁷R⁸)_(z)—, —C═O—, or —CR⁷R⁸(C═O)—, —O—, —SO—, or—SO₂—;

z is an integer from 0 to 10;

q is an integer from 0 to 5;

each R⁶ is independently hydrogen, halogen, —CN, —OR¹⁰, —S(O)_(n)R¹¹,—NR¹²R¹³, —C(O)R¹⁴, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl, wherein n is independently aninteger from 0 to 2;

each of R⁷ and R⁸ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocyclyalkyl, or R⁷ and R⁸ taken together form acycloalkyl, heterocycloalkyl or aryl ring;

R⁹ is hydrogen, —C(O)R¹⁴, alkyl, alkenyl, alkynyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R¹⁰ is independently hydrogen, —C(O)R¹⁵, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R¹¹ is independently —NR¹⁶R¹⁷, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each R¹² is independently hydrogen, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each R¹³ is independently hydrogen, —S(O)R¹⁸, —C(O)R¹⁹, alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

or R¹² and R¹³ are taken together to form a 5, 6, 7, or 8 membered ring,wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ringheteroatoms selected from N, S, or O in addition to the nitrogen atom of—NR¹²R¹³, and further wherein the 5, 6, 7, or 8 membered ring isoptionally substituted;

each R¹⁴ is independently —NR²⁰R²¹, hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R¹⁵ is independently —NR²²R²³, hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each of R¹⁶ and R¹⁷ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R¹⁶ and R¹⁷ aretaken together to form a 5, 6, 7 or 8 membered ring, wherein the 5, 6,7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selectedfrom N, S, or O in addition to the nitrogen atom of —NR¹⁶R¹⁷, andfurther wherein the 5, 6, 7, or 8 membered ring is optionallysubstituted;

each R¹⁸ is independently hydrogen, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl;

each R¹⁹ is independently —NR²⁴R²⁵, hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each of R²⁰ and R²¹ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R²⁰ and R²¹ aretaken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6,7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selectedfrom N, S, or O in addition to the nitrogen atom of —NR²⁰R²¹, andfurther wherein the 5, 6, 7, or 8 membered ring is optionallysubstituted;

each of R²² and R²³ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R²² and R²³ aretaken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6,7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selectedfrom N, S, or O in addition to the nitrogen atom of —NR²²R²³, andfurther wherein the 5, 6, 7, or 8 membered ring is optionallysubstituted; and

each of R²⁴ and R²⁵ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R²⁴ and R²⁵ aretaken together to form a 5, 6, 7, or 8 membered ring wherein the 5, 6,7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selectedfrom N, S, or O in addition to the nitrogen atom of —NR²⁴R²⁵, andfurther wherein the 5, 6, 7, or 8 membered ring is optionallysubstituted.

In some embodiments, the compound of Formula V-A is a compound havingthe structure of Formula V-A1:

In some embodiments, the compound of Formula V-A, Formula V-B, FormulaV-C or Formula V-D is a compound having a structure of one of thefollowing formulae:

In some embodiments, a compound of Formula VI-A is a compound having astructure of Formula VI-A1 or Formula VI-A2:

In some other embodiments, the compound of Formula V-A, Formula V-B,Formula V-C or Formula V-D is a compound having a structure of one ofthe following formulae:

In some embodiments, a compound of Formula VI-A is a compound having astructure of Formula VI-A1 or Formula VI-A2:

In some embodiments of the compound of Formula I-A, I-B, I-C, I-D, I-E,I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A,V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A,VII-A1, VII-A2, VII-B, VII-C, or VII-D, L is a group of the formula—(CR⁷R⁸)_(z)—, where z is an integer from 0 to 10. In some embodiments,z is 1, 2 or 3. For example, z may be 1. Each R⁷ and R⁸ is independentlyhydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyalkyl, or R⁷ and R⁸taken together form a cycloalkyl, heterocycloalkyl or aryl ring. In someembodiments, L is methylene or ethylene. In other embodiments, L ismethylene or ethylene substituted with additional alkyl groups such asmethyl, ethyl or isopropyl.

In some embodiments of the compound of Formula I-A, I-B, I-C, I-D, I-E,I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A,V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A,VII-A1, VII-A2, VII-B, VII-C, or VII-D, R¹ is halogen, —CN, —OR^(l0),—S(O)_(n)R¹¹, —NR¹²R¹³, —C(O)R⁴, alkyl, alkenyl, alkynyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein n isindependently an integer from 0 to 2. For example, R¹ may be anmonocyclic aryl group, that can be substituted or is unsubstituted; abicyclic aryl group, that can be substituted or unsubstituted; amonocyclic heteroaryl group, that can be substituted or isunsubstituted; or a bicyclic heteroaryl group, that can be substitutedor is unsubstituted. In other embodiments, R¹ may be a monocyclicheterocycloalkyl group, that can be substituted or is unsubstituted; abicyclic heterocycloalkyl group, that can be substituted or isunsubstituted; a heteroalkyl group, that can be substituted or isunsubstituted; or an alkyl group, that can be substituted or isunsubstituted. In some embodiments, R¹ is substituted with halogen, —CN,—OR¹⁰, —S(O)_(n)R¹¹, —NR¹²R¹³, —C(O)R¹⁴, alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In someembodiments, R¹ is an aryl group substituted with —C(O)R¹⁴. In otherembodiments, R¹ is a heteroaryl group substituted with halogen or—NR¹²R¹³. When R¹ is a monocyclic aromatic or heteroaryl group,substitutions on R¹ may be effected, for example, at the ortho, metaand/or para positions. In some embodiments, R¹ is monocyclic aryl. Inother embodiments, R¹ is bicyclic aryl.

Additional examples of R¹ groups are illustrated below:

In some embodiments of the compound of Formula I-A, I-B, I-C, I-D, I-E,I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A,V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A,VII-A1, VII-A2, VII-B, VII-C, or VII-D, L¹ may be a bond or a linkerconnecting R¹ to a heterocyclic moiety of the compounds of theinvention. In some embodiments, L¹ is a bond. In other embodiments, L¹is an alkylene group.

In some embodiments of the compound of Formula I-A, I-B, I-C, I-D, I-E,I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A,V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A,VII-A1, VII-A2, VII-B, VII-C, or VII-D, R⁴ and R⁵ are independentlyhydrogen. Alternatively, R⁴ and R⁵ taken together form a 5, 6 or7-membered ring, unsubstituted or substituted with (R⁶)_(q). In someembodiments, R⁴ and R⁵ taken together form a 5 or 6-memberedunsubstituted or substituted with (R⁶)_(q). The ring may be saturated,unsaturated, or partially unsaturated, and may be aromatic ornonaromatic. In some embodiments, the ring is aromatic and substitutedby R⁶. In some embodiments, R⁴ and R⁵ taken together form a group havinga structure of one of the following formulae:

In some embodiments of the compound of Formula I-A, I-B, I-C, I-D, I-E,I-F, I-G, I-H, I-J, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1,V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1,VII-A2, VII-B, VII-C, or VII-D, R⁶ may be any substituent such ashalogen, —CN, —OR¹⁰, —S(O)_(n)R¹¹, —NR¹²R¹³, —C(O)R¹⁴, alkyl, alkenyl,alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,wherein n is independently an integer from 0 to 2. In some embodiments,R⁶ is halogen. Alternatively, R⁶ is an alkyl group such as methyl. Infurther embodiments, R⁶ is a substituted alkyl group such as CF₃.

In some embodiments of the compound of Formula I-A, I-B, I-C, I-D, I-E,I-F, I-G, I-H, I-J, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1,V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1,VII-A2, VII-B, VII-C, or VII-D, R⁹ may be any cyclic, linear or branchedsubstituent. In some embodiments, R⁹ is halogen, —CN, —OR¹⁰,—S(O)_(n)R¹¹, —NR¹²R¹³, —C(O)R¹⁴, allyl, alkenyl, alkynyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein n isindependently an integer from 0 to 2. For example, R⁹ may be anmonocyclic aryl group, substituted or unsubstituted; a bicyclic arylgroup, substituted or unsubstituted; a monocyclic heteroaryl group,substituted or unsubstituted; a bicyclic heteroaryl group, substitutedor unsubstituted; a monocyclic heterocycloalkyl group, substituted orunsubstituted; a bicyclic heterocycloalkyl group, substituted orunsubstituted; a heteroalkyl group, substituted or unsubstituted; analkyl group, substituted or unsubstituted. In some embodiments, R⁹ issubstituted with halogen, —CN, —OR¹⁰, —S(O)_(n)R¹¹, —NR¹²R¹³, —C(O)R¹⁴,alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl,aryl, or heteroaryl.

In some embodiments, R⁹ is any of the groups shown below:

In some embodiments of the compound of Formula I-A, I-B, I-C, I-D, I-E,I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A,V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A,VII-A1, VII-A2, VII-B, VII-C, or VII-D, R¹² and R¹³ in —NR¹²R¹³, R¹⁶ andR¹⁷ in —NR¹⁶R¹⁷, R²⁰ and R²¹ in —NR²⁰R²¹, R²² and R²³ in —NR²²R²³, orR²⁴ and R²⁵ i-NR²⁴R²⁵, are taken together with the nitrogen atom towhich they are attached to form a 5-8 membered saturated or unsaturatedring; wherein said ring is independently unsubstituted or is substitutedby one or more —NR¹²R¹³, hydroxyl, halogen, oxo, aryl, hetaryl,C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl, —OPO₃H₂ or —O-aryl, and wherein said 5-8membered saturated or unsaturated ring independently contains 0, 1, or 2more heteroatoms selected from N, O, or S in addition to the nitrogen.

In some embodiments, R¹² and R¹³ in —NR¹²R¹³, R¹⁶ and R¹⁷ in —NR¹⁶R¹⁷,R²⁰ and R²¹ in —NR²OR²¹, R²² and R²³ in —NR²²R²³, or R²⁴ and R²⁵i-NR²⁴R²⁵, are taken together with the nitrogen atom to which they areattached to form a moiety of one of the following formulae:

In some embodiments, the compound of the invention comprises aheterocyclic subunit of the formulas Za or Zb shown below. The symbol

represents the point of attachment to the linker L. In specificembodiments, the point of attachment to the linker L is X⁴ or theexocyclic amine moiety. Additional substituents may be present at any orseveral of the X¹, X², X⁴, X⁵, and X⁶ positions. For example, an R¹group as defined above may be connected to X⁶.

TABLE 1 Heterocyclic subunits of the compounds of the invention. ″C″represents —CH═ or >C═, and ″N″ represents —N═, —N< or —NH— as requiredfor proper valency. Any illustrated subunit Z may be combined with theembodiments disclosed for R¹ through R⁹, L and W to design a compound ofthe invention Core X₁ X₂ X₃ X₄ X₅ X₆ X₇ Z-l C C C C C C C Z-2 C C C N CC C Z-3 C C C C C N C Z-4 C C C C N C C Z-5 C C N C C C C Z-6 C C C C CC N Z-7 C N C N C C C Z-8 C N C C C N C Z-9 C N C C N C C Z-10 C N N C CC C Z-11 C N C C C C N Z-12 N C C N C C C Z-13 N C C C C N C Z-14 N C CC N C C Z-15 N C N C C C C Z-16 N C C C C C N Z-17 C C C C N N C Z-18 CC C N N C C Z-19 C N C C N N C Z-20 C N C N N C C Z-21 N C C C N N CZ-22 N C C N N C C Z-23 N C C C N C N Z-24 C N C C N C N Z-25 C C C C NC N Z-26 C C N C N C C Z-27 N C N C N C C Z-28 C C N N C C C

Non-limiting examples of compounds of the invention are described inmore detail in Tables 2-5 below.

TABLE 2 Exemplary compounds of Formula II-A, wherein X represents Cl,Br, or F. R¹ R⁹ No

     R⁶      H  Me X    W    C     N   R⁷    H Me  Et

2-1 X X X X X 2-2 X X X X X 2-3 X X X X X 2-4 X X X X X 2-5 X X X X X2-6 X X X X X 2-7 X X X X X 2-8 X X X X X 2-9 X X X X X 2-10 X X X X X2-11 X X X X X 2-12 X X X X X 2-13 X X X X X 2-14 X X X X X 2-15 X X X XX 2-16 X X X X X 2-17 X X X X X 2-18 X X X X X 2-19 X X X X X 2-20 X X XX X 2-21 X X X X X 2-22 X X X X X 2-23 X X X X X 2-24 X X X X X 2-25 X XX X X 2-26 X X X X X 2-27 X X X X X 2-28 X X X X X 2-29 X X X X X 2-30 XX X X X 2-31 X X X X X 2-32 X X X X X 2-33 X X X X X 2-34 X X X X X 2-35X X X X X 2-36 X X X X X 2-37 X X X X X 2-38 X X X X X 2-39 X X X X X2-40 X X X X X 2-41 X X X X X 2-42 X X X X X 2-43 X X X X X 2-44 X X X XX 2-45 X X X X X 2-46 X X X X X 2-47 X X X X X 2-48 X X X X X 2-49 X X XX X 2-50 X X X X X 2-51 X X X X X 2-52 X X X X X 2-53 X X X X X 2-54 X XX X X 2-55 X X X X X 2-56 X X X X X 2-57 X X X X X 2-58 X X X X X 2-59 XX X X X 2-60 X X X X X 2-61 X X X X X 2-62 X X X X X 2-63 X X X X X 2-64X X X X X 2-65 X X X X X 2-66 X X X X X 2-67 X X X X X 2-68 X X X X X2-69 X X X X X 2-70 X X X X X 2-71 X X X X X 2-72 X X X X X 2-73 X X X XX 2-74 X X X X X 2-75 X X X X X 2-76 X X X X X 2-77 X X X X X 2-78 X X XX X 2-79 X X X X X 2-80 X X X X X 2-81 X X X X X 2-82 X X X X X 2-83 X XX X X 2-84 X X X X X 2-85 X X X X X 2-86 X X X X X 2-87 X X X X X 2-88 XX X X X 2-89 X X X X X 2-90 X X X X X 2-91 X X X X X 2-92 X X X X X 2-93X X X X X 2-94 X X X X X 2-95 X X X X X 2-96 X X X X X 2-97 X X X X X2-98 X X X X X 2-99 X X X X X 2-100 X X X X X 2-101 X X X X X 2-102 X XX X X 2-103 X X X X X 2-104 X X X X X 2-105 X X X X X 2-106 X X X X X2-107 X X X X X 2-108 X X X X X 2-109 X X X X X 2-110 X X X X X 2-111 XX X X X 2-112 X X X X X 2-113 X X X X X 2-114 X X X X X 2-115 X X X X X2-116 X X X X X 2-117 X X X X X 2-118 X X X X X 2-119 X X X X X 2-120 XX X X X 2-121 X X X X X 2-122 X X X X X 2-123 X X X X X 2-124 X X X X X2-125 X X X X X 2-126 X X X X X 2-127 X X X X X 2-128 X X X X X 2-129 XX X X X 2-130 X X X X X 2-131 X X X X X 2-132 X X X X X 2-133 X X X X X2-134 X X X X X 2-135 X X X X X 2-136 X X X X X 2-137 X X X X X 2-138 XX X X X 2-139 X X X X X 2-140 X X X X X 2-141 X X X X X 2-142 X X X X X2-143 X X X X X 2-144 X X X X X 2-145 X X X X X 2-146 X X X X X 2-147 XX X X X 2-148 X X X X X 2-149 X X X X X 2-150 X X X X X 2-151 X X X X X2-152 X X X X X 2-153 X X X X X 2-154 X X X X X 2-155 X X X X X 2-156 XX X X X 2-157 X X X X X 2-158 X X X X X 2-159 X X X X X 2-160 X X X X X2-161 X X X X X 2-162 X X X X X 2-163 X X X X X 2-164 X X X X X 2-165 XX X X X 2-166 X X X X X 2-167 X X X X X 2-168 X X X X X 2-169 X X X X X2-170 X X X X X 2-171 X X X X X 2-172 X X X X X 2-173 X X X X X 2-174 XX X X X 2-175 X X X X X 2-176 X X X X X 2-177 X X X X X 2-178 X X X X X2-179 X X X X X 2-180 X X X X X 2-181 X X X X X 2-182 X X X X X 2-183 XX X X X 2-184 X X X X X 2-185 X X X X X 2-186 X X X X X 2-187 X X X X X2-188 X X X X X 2-189 X X X X X 2-190 X X X X X 2-191 X X X X X 2-192 XX X X X 2-193 X X X X X 2-194 X X X X X 2-195 X X X X X 2-196 X X X X X2-197 X X X X X 2-198 X X X X X 2-199 X X X X X 2-200 X X X X X 2-201 XX X X X 2-202 X X X X X 2-203 X X X X X 2-204 X X X X X 2-205 X X X X X2-206 X X X X X 2-207 X X X X X 2-208 X X X X X 2-209 X X X X X 2-210 XX X X X 2-211 X X X X X 2-212 X X X X X 2-213 X X X X X 2-214 X X X X X2-215 X X X X X 2-216 X X X X X 2-217 X X X X X 2-218 X X X X X 2-219 XX X X X 2-220 X X X X X 2-221 X X X X X 2-222 X X X X X 2-223 X X X X X2-224 X X X X X 2-225 X X X X X 2-226 X X X X X 2-227 X X X X X 2-228 XX X X X 2-229 X X X X X 2-230 X X X X X 2-231 X X X X X 2-232 X X X X X2-233 X X X X X 2-234 X X X X X 2-235 X X X X X 2-236 X X X X X 2-237 XX X X X 2-238 X X X X X 2-239 X X X X X 2-240 X X X X X 2-241 X X X X X2-242 X X X X X 2-243 X X X X X 2-244 X X X X X 2-245 X X X X X 2-246 XX X X X 2-247 X X X X X 2-248 X X X X X 2-249 X X X X X 2-250 X X X X X2-251 X X X X X 2-252 X X X X X 2-253 X X X X X 2-254 X X X X X 2-255 XX X X X 2-256 X X X X X 2-257 X X X X X 2-258 X X X X X 2-259 X X X X X2-260 X X X X X 2-261 X X X X X 2-262 X X X X X 2-263 X X X X X 2-264 XX X X X 2-265 X X X X X 2-266 X X X X X 2-267 X X X X X 2-268 X X X X X2-269 X X X X X 2-270 X X X X X 2-271 X X X X X 2-272 X X X X X 2-273 XX X X X 2-274 X X X X X 2-275 X X X X X 2-276 X X X X X 2-277 X X X X X2-278 X X X X X 2-279 X X X X X 2-280 X X X X X 2-281 X X X X X 2-282 XX X X X 2-283 X X X X X 2-284 X X X X X 2-285 X X X X X 2-286 X X X X X2-287 X X X X X 2-288 X X X X X 2-289 X X X X X 2-290 X X X X X 2-291 XX X X X 2-292 X X X X X 2-293 X X X X X 2-294 X X X X X 2-295 X X X X X2-296 X X X X X 2-297 X X X X X 2-298 X X X X X 2-299 X X X X X 2-300 XX X X X 2-301 X X X X X 2-302 X X X X X 2-303 X X X X X 2-304 X X X X X2-305 X X X X X 2-306 X X X X X 2-307 X X X X X 2-308 X X X X X 2-309 XX X X X 2-310 X X X X X 2-311 X X X X X 2-312 X X X X X 2-313 X X X X X2-314 X X X X X 2-315 X X X X X 2-316 X X X X X 2-317 X X X X X 2-318 XX X X X 2-319 X X X X X 2-320 X X X X X 2-321 X X X X X 2-322 X X X X X2-323 X X X X X 2-324 X X X X X 2-325 X X X X X 2-326 X X X X X 2-327 XX X X X 2-328 X X X X X 2-329 X X X X X 2-330 X X X X X 2-331 X X X X X2-332 X X X X X 2-333 X X X X X 2-334 X X X X X 2-335 X X X X X 2-336 XX X X X 2-337 X X X X X 2-338 X X X X X 2-339 X X X X X 2-340 X X X X X2-341 X X X X X 2-342 X X X X X 2-343 X X X X X 2-344 X X X X X 2-345 XX X X X 2-346 X X X X X 2-347 X X X X X 2-348 X X X X X 2-349 X X X X X2-350 X X X X X 2-351 X X X X X 2-352 X X X X X 2-353 X X X X X 2-354 XX X X X 2-355 X X X X X 2-356 X X X X X 2-357 X X X X X 2-358 X X X X X2-359 X X X X X 2-360 X X X X X 2-361 X X X X X 2-362 X X X X X 2-363 XX X X X 2-364 X X X X X 2-365 X X X X X 2-366 X X X X X 2-367 X X X X X2-368 X X X X X 2-369 X X X X X 2-370 X X X X X 2-371 X X X X X 2-372 XX X X X 2-373 X X X X X 2-374 X X X X X 2-375 X X X X X 2-376 X X X X X2-377 X X X X X 2-378 X X X X X 2-379 X X X X X 2-380 X X X X X 2-381 XX X X X 2-382 X X X X X 2-383 X X X X X 2-384 X X X X X 2-385 X X X X X2-386 X X X X X 2-387 X X X X X 2-388 X X X X X 2-389 X X X X X 2-390 XX X X X 2-391 X X X X X 2-392 X X X X X 2-393 X X X X X 2-394 X X X X X2-395 X X X X X 2-396 X X X X X 2-397 X X X X X 2-398 X X X X X 2-399 XX X X X 2-400 X X X X X 2-401 X X X X X 2-402 X X X X X 2-403 X X X X X2-404 X X X X X 2-405 X X X X X 2-406 X X X X X 2-407 X X X X X 2-408 XX X X X 2-409 X X X X X 2-410 X X X X X 2-411 X X X X X 2-412 X X X X X2-413 X X X X X 2-414 X X X X X 2-415 X X X X X 2-416 X X X X X 2-417 XX X X X 2-418 X X X X X 2-419 X X X X X 2-420 X X X X X 2-421 X X X X X2-422 X X X X X 2-423 X X X X X 2-424 X X X X X 2-425 X X X X X 2-426 XX X X X 2-427 X X X X X 2-428 X X X X X 2-429 X X X X X 2-430 X X X X2-431 X X X X X X 2-432 X X X X X 2-433 X X X X X 2-434 X X X X X 2-435X X X X X 2-436 X X X X X 2-437 X X X X X 2-438 X X X X X 2-439 X X X XX 2-440 X X X X X 2-441 X X X X X 2-442 X X X X X 2-443 X X X X X 2-444X X X X X 2-445 X X X X X 2-446 X X X X X 2-447 X X X X X 2-448 X X X XX 2-449 X X X X X 2-450 X X X X X 2-451 X X X X X 2-452 X X X X X 2-453X X X X X 2-454 X X X X X 2-455 X X X X X 2-456 X X X X X 2-457 X X X XX 2-458 X X X X X 2-459 X X X X X 2-460 X X X X X 2-461 X X X X X 2-462X X X X X 2-463 X X X X X 2-464 X X X X X 2-465 X X X X X 2-466 X X X XX 2-467 X X X X X 2-468 X X X X X 2-469 X X X X X 2-470 X X X X X 2-471X X X X X 2-472 X X X X X 2-473 X X X X X 2-474 X X X X X 2-475 X X X XX 2-476 X X X X X 2-477 X X X X X 2-478 X X X X X 2-479 X X X X X 2-480X X X X X 2-481 X X X X X 2-482 X X X X X 2-483 X X X X X 2-484 X X X XX 2-485 X X X X X 2-486 X X X X X 2-487 X X X X X 2-488 X X X X X 2-489X X X X X 2-490 X X X X X 2-491 X X X X X 2-492 X X X X X 2-493 X X X XX 2-494 X X X X X 2-495 X X X X X 2-496 X X X X X 2-497 X X X X X 2-498X X X X X 2-499 X X X X X 2-500 X X X X X 2-501 X X X X X 2-502 X X X XX 2-503 X X X X X 2-504 X X X X X 2-505 X X X X X 2-506 X X X X X 2-507X X X X X 2-508 X X X X X 2-509 X X X X X 2-510 X X X X X 2-511 X X X XX 2-512 X X X X X 2-513 X X X X X 2-514 X X X X X 2-515 X X X X X 2-516X X X X X 2-517 X X X X X 2-518 X X X X X 2-519 X X X X X 2-520 X X X XX 2-521 X X X X X 2-522 X X X X X 2-523 X X X X X 2-524 X X X X X 2-525X X X X X 2-526 X X X X X 2-527 X X X X X 2-528 X X X X X 2-529 X X X XX 2-530 X X X X X 2-531 X X X X X 2-532 X X X X X 2-533 X X X X X 2-534X X X X X 2-535 X X X X X 2-536 X X X X X 2-537 X X X X X 2-538 X X X XX 2-539 X X X X X 2-540 X X X X X

TABLE 3 Exemplary compounds of the invention of Formula III-A, wherein Xrepresents a halo group (Cl, Br, I or F). Formula III-A

No. R¹ W R⁷ R⁹

C N H Me Et

3-1 X X X X 3-2 X X X X 3-3 X X X X X 3-4 X X X X 3-5 X X X X 3-6 X X XX 3-7 X X X X 3-8 X X X X 3-9 X X X X 3-10 X X X X 3-11 X X X X 3-12 X XX X 3-13 X X X X 3-14 X X X X 3-15 X X X X 3-16 X X X X 3-17 X X X X3-18 X X X X 3-19 X X X X 3-20 X X X X 3-21 X X X X 3-22 X X X X 3-23 XX X X 3-24 X X X X 3-25 X X X X 3-26 X X X X 3-27 X X X X 3-28 X X X X3-29 X X X X 3-30 X X X X 3-31 X X X X 3-32 X X X X 3-33 X X X X 3-34 XX X X 3-35 X X X X 3-36 X X X X 3-37 X X X X 3-38 X X X X 3-39 X X X X3-40 X X X X 3-41 X X X X 3-42 X X X X 3-43 X X X X 3-44 X X X X 3-45 XX X X 3-46 X X X X 3-47 X X X X 3-48 X X X X 3-49 X X X X 3-50 X X X X3-51 X X X X 3-52 X X X X 3-53 X X X X 3-54 X X X X 3-55 X X X X 3-56 XX X X 3-57 X X X X 3-58 X X X X 3-59 X X X X 3-60 X X X X 3-61 X X X X3-62 X X X X 3-63 X X X X 3-64 X X X X 3-65 X X X X 3-66 X X X X 3-67 XX X X 3-68 X X X X 3-69 X X X X 3-70 X X X X 3-71 X X X X 3-72 X X X X3-73 X X X X 3-74 X X X X 3-75 X X X X 3-76 X X X X 3-77 X X X X 3-78 XX X X 3-79 X X X X 3-80 X X X X 3-81 X X X X 3-82 X X X X 3-83 X X X X3-84 X X X X 3-85 X X X X 3-86 X X X X 3-87 X X X X 3-88 X X X X 3-89 XX X X 3-90 X X X X 3-91 X X X X 3-92 X X X X 3-93 X X X X 3-94 X X X X3-95 X X X X 3-96 X X X X 3-97 X X X X 3-98 X X X X 3-99 X X X X 3-100 XX X X 3-101 X X X X 3-102 X X X X 3-103 X X X X 3-104 X X X X 3-105 X XX X 3-106 X X X X 3-107 X X X X 3-108 X X X X 3-109 X X X X 3-110 X X XX 3-111 X X X X 3-112 X X X X 3-113 X X X X 3-114 X X X X 3-115 X X X X3-116 X X X X 3-117 X X X X 3-118 X X X X 3-119 X X X X 3-120 X X X X3-121 X X X X 3-122 X X X X 3-123 X X X X 3-124 X X X X 3-125 X X X X3-126 X X X X 3-127 X X X X 3-128 X X X X 3-129 X X X X 3-130 X X X X3-131 X X X X 3-132 X X X X 3-133 X X X X 3-134 X X X X 3-135 X X X X3-136 X X X X 3-137 X X X X 3-138 X X X X 3-139 X X X X 3-140 X X X X3-141 X X X X 3-142 X X X X 3-143 X X X X 3-144 X X X X 3-145 X X X X3-146 X X X X 3-147 X X X X 3-148 X X X X 3-149 X X X X 3-150 X X X X3-151 X X X X 3-152 X X X X 3-153 X X X X 3-154 X X X X 3-155 X X X X3-156 X X X X 3-157 X X X X 3-158 X X X X 3-159 X X X X 3-160 X X X X3-161 X X X X 3-162 X X X X 3-163 X X X X 3-164 X X X X 3-165 X X X X3-166 X X X X 3-167 X X X X 3-168 X X X X 3-169 X X X X 3-170 X X X X3-171 X X X X 3-172 X X X X 3-173 X X X X 3-174 X X X X 3-175 X X X X3-176 X X X X 3-177 X X X X 3-178 X X X X 3-179 X X X X 3-180 X X X X3-181 X X X X 3-182 X X X X 3-183 X X X X 3-184 X X X X 3-185 X X X X3-186 X X X X 3-187 X X X X 3-188 X X X X 3-189 X X X X 3-190 X X X X3-191 X X X X 3-192 X X X X 3-193 X X X X 3-194 X X X X 3-195 X X X X3-196 X X X X 3-197 X X X X 3-198 X X X X 3-199 X X X X 3-200 X X X X3-201 X X X X 3-202 X X X X 3-203 X X X X 3-204 X X X X 3-205 X X X X3-206 X X X X 3-207 X X X X 3-208 X X X X 3-209 X X X X 3-210 X X X X3-211 X X X X 3-212 X X X X 3-213 X X X X 3-214 X X X X 3-215 X X X X3-216 X X X X 3-217 X X X X 3-218 X X X X 3-219 X X X X 3-220 X X X X3-221 X X X X 3-222 X X X X 3-223 X X X X 3-224 X X X X 3-225 X X X X3-226 X X X X 3-227 X X X X 3-228 X X X X 3-229 X X X X 3-230 X X X X3-231 X X X X 3-232 X X X X 3-233 X X X X 3-234 X X X X 3-235 X X X X3-236 X X X X 3-237 X X X X 3-238 X X X X 3-239 X X X X 3-240 X X X X3-241 X X X X 3-242 X X X X 3-243 X X X X 3-244 X X X X 3-245 X X X X3-246 X X X X 3-247 X X X X 3-248 X X X X 3-249 X X X X 3-250 X X X X3-251 X X X X 3-252 X X X X 3-253 X X X X 3-254 X X X X 3-255 X X X X3-256 X X X X 3-257 X X X X 3-258 X X X X 3-259 X X X X 3-260 X X X X3-261 X X X X 3-262 X X X X 3-263 X X X X 3-264 X X X X 3-265 X X X X3-266 X X X X 3-267 X X X X 3-268 X X X X 3-269 X X X X 3-270 X X X XNo. R¹ W R⁷ R⁹

C N H Me Et

3-271 X X X X 3-272 X X X X 3-273 X X X X 3-274 X X X X 3-275 X X X X3-276 X X X X 3-277 X X X X 3-278 X X X X 3-279 X X X X 3-280 X X X X3-281 X X X X 3-282 X X X X 3-283 X X X X 3-284 X X X X 3-285 X X X X3-286 X X X X 3-287 X X X X 3-288 X X X X 3-289 X X X X 3-290 X X X X3-291 X X X X 3-292 X X X X 3-293 X X X X 3-294 X X X X 3-295 X X X X3-296 X X X X 3-297 X X X X 3-298 X X X X 3-299 X X X X 3-300 X X X X3-301 X X X X 3-302 X X X X 3-303 X X X X 3-304 X X X X 3-305 X X X X3-306 X X X X 3-307 X X X X 3-308 X X X X 3-309 X X X X 3-310 X X X X3-311 X X X X 3-312 X X X X 3-313 X X X X 3-314 X X X X 3-315 X X X X3-316 X X X X 3-317 X X X X 3-318 X X X X 3-319 X X X X 3-320 X X X X3-321 X X X X 3-322 X X X X 3-323 X X X X 3-324 X X X X 3-325 X X X X3-326 X X X X 3-327 X X X X 3-328 X X X X 3-329 X X X X 3-330 X X X X3-331 X X X X 3-332 X X X X 3-333 X X X X 3-334 X X X X 3-335 X X X X3-336 X X X X 3-337 X X X X 3-338 X X X X 3-339 X X X X 3-340 X X X X3-341 X X X X 3-342 X X X X 3-343 X X X X 3-344 X X X X 3-345 X X X X3-346 X X X X 3-347 X X X X 3-348 X X X X 3-349 X X X X 3-350 X X X X3-351 X X X X 3-352 X X X X 3-353 X X X X 3-354 X X X X 3-355 X X X X3-356 X X X X 3-357 X X X X 3-358 X X X X 3-359 X X X X 3-360 X X X X3-361 X X X X 3-362 X X X X 3-363 X X X X 3-364 X X X X 3-365 X X X X3-366 X X X X 3-367 X X X X 3-368 X X X X 3-369 X X X X 3-370 X X X X3-371 X X X X 3-372 X X X X 3-373 X X X X 3-374 X X X X 3-375 X X X X3-376 X X X X 3-377 X X X X 3-378 X X X X 3-379 X X X X 3-380 X X X X3-381 X X X X 3-382 X X X X 3-383 X X X X 3-384 X X X X 3-385 X X X X3-386 X X X X 3-387 X X X X 3-388 X X X X 3-389 X X X X 3-390 X X X X3-391 X X X X 3-392 X X X X 3-393 X X X X 3-394 X X X X 3-395 X X X X3-396 X X X X 3-397 X X X X 3-398 X X X X 3-399 X X X X 3-400 X X X X3-401 X X X X 3-402 X X X X 3-403 X X X X 3-404 X X X X 3-405 X X X X3-406 X X X X 3-407 X X X X 3-408 X X X X 3-409 X X X X 3-410 X X X X3-411 X X X X 3-412 X X X X 3-413 X X X X 3-414 X X X X 3-415 X X X X3-416 X X X X 3-417 X X X X 3-418 X X X X 3-419 X X X X 3-420 X X X X3-421 X X X X 3-422 X X X X 3-423 X X X X 3-424 X X X X 3-425 X X X X3-426 X X X X 3-427 X X X X 3-428 X X X X 3-429 X X X X 3-430 X X X X3-431 X X X X 3-432 X X X X 3-433 X X X X 3-434 X X X X 3-435 X X X X3-436 X X X X 3-437 X X X X 3-438 X X X X 3-439 X X X X 3-440 X X X X3-441 X X X X 3-442 X X X X 3-443 X X X X 3-444 X X X X 3-445 X X X X3-446 X X X X 3-447 X X X X 3-448 X X X X 3-449 X X X X 3-450 X X X X3-451 X X X X 3-452 X X X X 3-453 X X X X 3-454 X X X X 3-455 X X X X3-456 X X X X 3-457 X X X X 3-458 X X X X 3-459 X X X X 3-460 X X X X3-461 X X X X 3-462 X X X X 3-463 X X X X 3-464 X X X X 3-465 X X X X3-466 X X X X 3-467 X X X X 3-468 X X X X 3-469 X X X X 3-470 X X X X3-471 X X X X 3-472 X X X X 3-473 X X X X 3-474 X X X X 3-475 X X X X3-476 X X X X 3-477 X X X X 3-478 X X X X 3-479 X X X X 3-480 X X X X3-481 X X X X 3-482 X X X X 3-483 X X X X 3-484 X X X X 3-485 X X X X3-486 X X X X 3-487 X X X X 3-488 X X X X 3-489 X X X X 3-490 X X X X3-491 X X X X 3-492 X X X X 3-493 X X X X 3-494 X X X X 3-495 X X X X3-496 X X X X 3-497 X X X X 3-498 X X X X 3-499 X X X X 3-500 X X X X3-501 X X X X 3-502 X X X X 3-503 X X X X 3-504 X X X X 3-505 X X X X3-506 X X X X 3-507 X X X X 3-508 X X X X 3-509 X X X X 3-510 X X X X3-511 X X X X 3-512 X X X X 3-513 X X X X 3-514 X X X X 3-515 X X X X3-516 X X X X 3-517 X X X X 3-518 X X X X 3-519 X X X X 3-520 X X X X3-521 X X X X 3-522 X X X X 3-523 X X X X 3-524 X X X X 3-525 X X X X3-526 X X X X 3-527 X X X X 3-528 X X X X 3-529 X X X X 3-530 X X X X3-531 X X X X 3-532 X X X X 3-533 X X X X 3-534 X X X X 3-535 X X X X3-536 X X X X 3-537 X X X X 3-538 X X X X 3-539 X X X X 3-540 X X X X

TABLE 4 Exemplary compounds of the invention of Formula IV-A. FormulaIV-A

No. R¹ W R⁷ R⁹

C N H Me Et

4-1 X X X X 4-2 X X X X 4-3 X X X X 4-4 X X X X 4-5 X X X X 4-6 X X X X4-7 X X X X 4-8 X X X X 4-9 X X X X 4-10 X X X X 4-11 X X X X 4-12 X X XX 4-13 X X X X 4-14 X X X X 4-15 X X X X 4-16 X X X X 4-17 X X X X 4-18X X X X 4-19 X X X X 4-20 X X X X 4-21 X X X X 4-22 X X X X 4-23 X X X X4-24 X X X X 4-25 X X X X 4-26 X X X X 4-27 X X X X 4-28 X X X X 4-29 XX X X 4-30 X X X X 4-31 X X X X 4-32 X X X X 4-33 X X X X 4-34 X X X X4-35 X X X X 4-36 X X X X 4-37 X X X X 4-38 X X X X 4-39 X X X X 4-40 XX X X 4-41 X X X X 4-42 X X X X 4-43 X X X X 4-44 X X X X 4-45 X X X X4-46 X X X X 4-47 X X X X 4-48 X X X X 4-49 X X X X 4-50 X X X X 4-51 XX X X 4-52 X X X X 4-53 X X X X 4-54 X X X X 4-55 X X X X 4-56 X X X X4-57 X X X X 4-58 X X X X 4-59 X X X X 4-60 X X X X 4-61 X X X X 4-62 XX X X 4-63 X X X X 4-64 X X X X 4-65 X X X X 4-66 X X X X 4-67 X X X X4-68 X X X X 4-69 X X X X 4-70 X X X X 4-71 X X X X 4-72 X X X X 4-73 XX X X 4-74 X X X X 4-75 X X X X 4-76 X X X X 4-77 X X X X 4-78 X X X X4-79 X X X X 4-80 X X X X 4-81 X X X X 4-82 X X X X 4-83 X X X X 4-84 XX X X 4-85 X X X X 4-86 X X X X 4-87 X X X X 4-88 X X X X 4-89 X X X X4-90 X X X X 4-91 X X X X 4-92 X X X X 4-93 X X X X 4-94 X X X X 4-95 XX X X 4-96 X X X X 4-97 X X X X 4-98 X X X X 4-99 X X X X 4-100 X X X X4-101 X X X X 4-102 X X X X 4-103 X X X X 4-104 X X X X 4-105 X X X X4-106 X X X X 4-107 X X X X 4-108 X X X X 4-109 X X X X 4-110 X X X X4-111 X X X X 4-112 X X X X 4-113 X X X X 4-114 X X X X 4-115 X X X X4-116 X X X X 4-117 X X X X 4-118 X X X X 4-119 X X X X 4-120 X X X X4-121 X X X X 4-122 X X X X 4-123 X X X X 4-124 X X X X 4-125 X X X X4-126 X X X X 4-127 X X X X 4-128 X X X X 4-129 X X X X 4-130 X X X X4-131 X X X X 4-132 X X X X 4-133 X X X X 4-134 X X X X 4-135 X X X X4-136 X X X X 4-137 X X X X 4-138 X X X X 4-139 X X X X 4-140 X X X X4-141 X X X X 4-142 X X X X 4-143 X X X X 4-144 X X X X 4-145 X X X X4-146 X X X X 4-147 X X X X 4-148 X X X X 4-149 X X X X 4-150 X X X X4-151 X X X X 4-152 X X X X 4-153 X X X X 4-154 X X X X 4-155 X X X X4-156 X X X X 4-157 X X X X 4-158 X X X X 4-159 X X X X 4-160 X X X X4-161 X X X X 4-162 X X X X 4-163 X X X X 4-164 X X X X 4-165 X X X X4-166 X X X X 4-167 X X X X 4-168 X X X X 4-169 X X X X 4-170 X X X X4-171 X X X X 4-172 X X X X 4-173 X X X X 4-174 X X X X 4-175 X X X X4-176 X X X X 4-177 X X X X 4-178 X X X X 4-179 X X X X 4-180 X X X X4-181 X X X X 4-182 X X X X 4-183 X X X X 4-184 X X X X 4-185 X X X X4-186 X X X X 4-187 X X X X 4-188 X X X X 4-189 X X X X 4-190 X X X X4-191 X X X X 4-192 X X X X 4-193 X X X X 4-194 X X X X 4-195 X X X X4-196 X X X X 4-197 X X X X 4-198 X X X X 4-199 X X X X 4-200 X X X X4-201 X X X X 4-202 X X X X 4-203 X X X X 4-204 X X X X 4-205 X X X X4-206 X X X X 4-207 X X X X 4-208 X X X X 4-209 X X X X 4-210 X X X X4-211 X X X X 4-212 X X X X 4-213 X X X X 4-214 X X X X 4-215 X X X X4-216 X X X X 4-217 X X X X 4-218 X X X X 4-219 X X X X 4-220 X X X X4-221 X X X X 4-222 X X X X 4-223 X X X X 4-224 X X X X 4-225 X X X X4-226 X X X X 4-227 X X X X 4-228 X X X X 4-229 X X X X 4-230 X X X X4-231 X X X X 4-232 X X X X 4-233 X X X X 4-234 X X X X 4-235 X X X X4-236 X X X X 4-237 X X X X 4-238 X X X X 4-239 X X X X 4-240 X X X X4-241 X X X X 4-242 X X X X 4-243 X X X X 4-244 X X X X 4-245 X X X X4-246 X X X X 4-247 X X X X 4-248 X X X X 4-249 X X X X 4-250 X X X X4-251 X X X X 4-252 X X X X 4-253 X X X X 4-254 X X X X 4-255 X X X X4-256 X X X X 4-257 X X X X 4-258 X X X X 4-259 X X X X 4-260 X X X X4-261 X X X X 4-262 X X X X 4-263 X X X X 4-264 X X X X 4-265 X X X X4-266 X X X X 4-267 X X X X 4-268 X X X X 4-269 X X X X 4-270 X X X XNo. R¹ W R⁷ R⁹ C N H Me Et

4-271 X X X X 4-272 X X X X 4-273 X X X X 4-274 X X X X 4-275 X X X X4-276 X X X X 4-277 X X X X 4-278 X X X X 4-279 X X X X 4-280 X X X X4-281 X X X X 4-282 X X X X 4-283 X X X X 4-284 X X X X 4-285 X X X X4-286 X X X X 4-287 X X X X 4-288 X X X X 4-289 X X X X 4-290 X X X X4-291 X X X X 4-292 X X X X 4-293 X X X X 4-294 X X X X 4-295 X X X X4-296 X X X X 4-297 X X X X 4-298 X X X X 4-299 X X X X 4-300 X X X X4-301 X X X X 4-302 X X X X 4-303 X X X X 4-304 X X X X 4-305 X X X X4-306 X X X X 4-307 X X X X 4-308 X X X X 4-309 X X X X 4-310 X X X X4-311 X X X X 4-312 X X X X 4-313 X X X X 4-314 X X X X 4-315 X X X X4-316 X X X X 4-317 X X X X 4-318 X X X X 4-319 X X X X 4-320 X X X X4-321 X X X X 4-322 X X X X 4-323 X X X X 4-324 X X X X 4-325 X X X X4-326 X X X X 4-327 X X X X 4-328 X X X X 4-329 X X X X 4-330 X X X X4-331 X X X X 4-332 X X X X 4-333 X X X X 4-334 X X X X 4-335 X X X X4-336 X X X X 4-337 X X X X 4-338 X X X X 4-339 X X X X 4-340 X X X X4-341 X X X X 4-342 X X X X 4-343 X X X X 4-344 X X X X 4-345 X X X X4-346 X X X X 4-347 X X X X 4-348 X X X X 4-349 X X X X 4-350 X X X X4-351 X X X X 4-352 X X X X 4-353 X X X X 4-354 X X X X 4-355 X X X X4-356 X X X X 4-357 X X X X 4-358 X X X X 4-359 X X X X 4-360 X X X X4-361 X X X X 4-362 X X X X 4-363 X X X X 4-364 X X X X 4-365 X X X X4-366 X X X X 4-367 X X X X 4-368 X X X X 4-369 X X X X 4-370 X X X X4-371 X X X X 4-372 X X X X 4-373 X X X X 4-374 X X X X 4-375 X X X X4-376 X X X X 4-377 X X X X 4-378 X X X X 4-379 X X X X 4-380 X X X X4-381 X X X X 4-382 X X X X 4-383 X X X X 4-384 X X X X 4-385 X X X X4-386 X X X X 4-387 X X X X 4-388 X X X X 4-389 X X X X 4-390 X X X X4-391 X X X X 4-392 X X X X 4-393 X X X X 4-394 X X X X 4-395 X X X X4-396 X X X X 4-397 X X X X 4-398 X X X X 4-399 X X X X 4-400 X X X X4-401 X X X X 4-402 X X X X 4-403 X X X X 4-404 X X X X 4-405 X X X X4-406 X X X X 4-407 X X X X 4-408 X X X X 4-409 X X X X 4-410 X X X X4-411 X X X X 4-412 X X X X 4-413 X X X X 4-414 X X X X 4-415 X X X X4-416 X X X X 4-417 X X X X 4-418 X X X X 4-419 X X X X 4-420 X X X X4-421 X X X X 4-422 X X X X 4-423 X X X X 4-424 X X X X 4-425 X X X X4-426 X X X X 4-427 X X X X 4-428 X X X X 4-429 X X X X 4-430 X X X X4-431 X X X X 4-432 X X X X 4-433 X X X X 4-434 X X X X 4-435 X X X X4-436 X X X X 4-437 X X X X 4-438 X X X X 4-439 X X X X 4-440 X X X X4-441 X X X X 4-442 X X X X 4-443 X X X X 4-444 X X X X 4-445 X X X X4-446 X X X X 4-447 X X X X 4-448 X X X X 4-449 X X X X 4-450 X X X X4-451 X X X X 4-452 X X X X 4-453 X X X X 4-454 X X X X 4-455 X X X X4-456 X X X X 4-457 X X X X 4-458 X X X X 4-459 X X X X 4-460 X X X X4-461 X X X X 4-462 X X X X 4-463 X X X X 4-464 X X X X 4-465 X X X X4-466 X X X X 4-467 X X X X 4-468 X X X X 4-469 X X X X 4-470 X X X X4-471 X X X X 4-472 X X X X 4-473 X X X X 4-474 X X X X 4-475 X X X X4-476 X X X X 4-477 X X X X 4-478 X X X X 4-479 X X X X 4-480 X X X X4-481 X X X X 4-482 X X X X 4-483 X X X X 4-484 X X X X 4-485 X X X X4-486 X X X X 4-487 X X X X 4-488 X X X X 4-489 X X X X 4-490 X X X X4-491 X X X X 4-492 X X X X 4-493 X X X X 4-494 X X X X 4-495 X X X X4-496 X X X X 4-497 X X X X 4-498 X X X X 4-499 X X X X 4-500 X X X X4-501 X X X X 4-502 X X X X 4-503 X X X X 4-504 X X X X 4-505 X X X X4-506 X X X X 4-507 X X X X 4-508 X X X X 4-509 X X X X 4-510 X X X X4-511 X X X X 4-512 X X X X 4-513 X X X X 4-514 X X X X 4-515 X X X X4-516 X X X X 4-517 X X X X 4-518 X X X X 4-519 X X X X 4-520 X X X X4-521 X X X X 4-522 X X X X 4-523 X X X X 4-524 X X X X 4-525 X X X X4-526 X X X X 4-527 X X X X 4-528 X X X X 4-529 X X X X 4-530 X X X X4-531 X X X X 4-532 X X X X 4-533 X X X X 4-534 X X X X 4-535 X X X X4-536 X X X X 4-537 X X X X 4-538 X X X X 4-539 X X X X 4-540 X X X X Xrepresents a halo group (Cl, Br, I or F).

TABLE 5 Exemplary compounds of the invention of Formula V-A1. FormulaV-A1

R¹ No

    R⁶     H  Me  X   W   C  N     R⁷     H  Me  Et     R⁹     H  Me Et  i-Pr 5-1 X X X X X 5-2 X X X X X 5-3 X X X X X 5-4 X X X X X 5-5 X XX X 5-6 X X X X X 5-7 X X X X X 5-8 X X X X X 5-9 X X X X X 5-10 X X X X5-11 X X X X X 5-12 X X X X X 5-13 X X X X X 5-14 X X X X X 5-15 X X X X5-16 X X X X X 5-17 X X X X X 5-18 X X X X X 5-19 X X X X X 5-20 X X X X5-21 X X X X X 5-22 X X X X X 5-23 X X X X X 5-24 X X X X X 5-25 X X X X5-26 X X X X X 5-27 X X X X X 5-28 X X X X X 5-29 X X X X X 5-30 X X X X5-31 X X X X X 5-32 X X X X X 5-33 X X X X X 5-34 X X X X X 5-35 X X X X5-36 X X X X X 5-37 X X X X X 5-38 X X X X X 5-39 X X X X X 5-40 X X X X5-41 X X X X X 5-42 X X X X X 5-43 X X X X X 5-44 X X X X X 5-45 X X X X5-46 X X X X X 5-47 X X X X X 5-48 X X X X X 5-49 X X X X X 5-50 X X X X5-51 X X X X X 5-52 X X X X X 5-53 X X X X X 5-54 X X X X X 5-55 X X X X5-56 X X X X X 5-57 X X X X X 5-58 X X X X X 5-59 X X X X X 5-60 X X X X5-61 X X X X X 5-62 X X X X X 5-63 X X X X X 5-64 X X X X X 5-65 X X X X5-66 X X X X X 5-67 X X X X X 5-68 X X X X X 5-69 X X X X X 5-70 X X X X5-71 X X X X X 5-72 X X X X X 5-73 X X X X X 5-74 X X X X X 5-75 X X X X5-76 X X X X X 5-77 X X X X X 5-78 X X X X X 5-79 X X X X X 5-80 X X X X5-81 X X X X X 5-82 X X X X X 5-83 X X X X X 5-84 X X X X X 5-85 X X X X5-86 X X X X X 5-87 X X X X X 5-88 X X X X X 5-89 X X X X X 5-90 X X X X5-91 X X X X X 5-92 X X X X X 5-93 X X X X X 5-94 X X X X X 5-95 X X X X5-96 X X X X X 5-97 X X X X X 5-98 X X X X X 5-99 X X X X X 5-100 X X XX 5-101 X X X X X 5-102 X X X X X 5-103 X X X X X 5-104 X X X X X 5-105X X X X 5-106 X X X X X 5-107 X X X X X 5-108 X X X X X 5-109 X X X X X5-110 X X X X 5-111 X X X X X 5-112 X X X X X 5-113 X X X X X 5-114 X XX X X 5-115 X X X X 5-116 X X X X X 5-117 X X X X X 5-118 X X X X X5-119 X X X X X 5-120 X X X X 5-121 X X X X X 5-122 X X X X X 5-123 X XX X X 5-124 X X X X X 5-125 X X X X 5-126 X X X X X 5-127 X X X X X5-128 X X X X X 5-129 X X X X X 5-130 X X X X 5-131 X X X X X 5-132 X XX X X 5-133 X X X X X 5-134 X X X X X 5-135 X X X X 5-136 X X X X X5-137 X X X X X 5-138 X X X X X 5-139 X X X X X 5-140 X X X X 5-141 X XX X X 5-142 X X X X X 5-143 X X X X X 5-144 X X X X X 5-145 X X X X5-146 X X X X X 5-147 X X X X X 5-148 X X X X X 5-149 X X X X X 5-150 XX X X 5-151 X X X X X 5-152 X X X X X 5-153 X X X X X 5-154 X X X X X5-155 X X X X 5-156 X X X X X 5-157 X X X X X 5-158 X X X X X 5-159 X XX X X 5-160 X X X X 5-161 X X X X X 5-162 X X X X X 5-163 X X X X X5-164 X X X X X 5-165 X X X X 5-166 X X X X X 5-167 X X X X X 5-168 X XX X X 5-169 X X X X X 5-170 X X X X 5-171 X X X X X 5-172 X X X X X5-173 X X X X X 5-174 X X X X X 5-175 X X X X 5-176 X X X X X 5-177 X XX X X 5-178 X X X X X 5-179 X X X X X 5-180 X X X X 5-181 X X X X X5-182 X X X X X 5-183 X X X X X 5-184 X X X X X 5-185 X X X X 5-186 X XX X X 5-187 X X X X X 5-188 X X X X X 5-189 X X X X X 5-190 X X X X5-191 X X X X X 5-192 X X X X X 5-193 X X X X X 5-194 X X X X X 5-195 XX X X 5-196 X X X X X 5-197 X X X X X 5-198 X X X X X 5-199 X X X X X5-200 X X X X 5-201 X X X X X 5-202 X X X X X 5-203 X X X X X 5-204 X XX X X 5-205 X X X X 5-206 X X X X X 5-207 X X X X X 5-208 X X X X X5-209 X X X X X 5-210 X X X X 5-211 X X X X X 5-212 X X X X X 5-213 X XX X X 5-214 X X X X X 5-215 X X X X 5-216 X X X X X 5-217 X X X X X5-218 X X X X X 5-219 X X X X X 5-220 X X X X 5-221 X X X X X 5-222 X XX X X 5-223 X X X X X 5-224 X X X X X 5-225 X X X X 5-226 X X X X X5-227 X X X X X 5-228 X X X X X 5-229 X X X X X 5-230 X X X X 5-231 X XX X X 5-232 X X X X X 5-233 X X X X X 5-234 X X X X X 5-235 X X X X5-236 X X X X X 5-237 X X X X X 5-238 X X X X X 5-239 X X X X X 5-240 XX X X 5-241 X X X X X 5-242 X X X X X 5-243 X X X X X 5-244 X X X X X5-245 X X X X 5-246 X X X X X 5-247 X X X X X 5-248 X X X X X 5-249 X XX X X 5-250 X X X X 5-251 X X X X X 5-252 X X X X X 5-253 X X X X X5-254 X X X X X 5-255 X X X X 5-256 X X X X X 5-257 X X X X X 5-258 X XX X X 5-259 X X X X X 5-260 X X X X 5-261 X X X X X 5-262 X X X X X5-263 X X X X X 5-264 X X X X X 5-265 X X X X 5-266 X X X X X 5-267 X XX X X 5-268 X X X X X 5-269 X X X X X 5-270 X X X X 5-271 X X X X X5-272 X X X X X 5-273 X X X X X 5-274 X X X X X 5-275 X X X X 5-276 X XX X X 5-277 X X X X X 5-278 X X X X X 5-279 X X X X X 5-280 X X X X5-281 X X X X X 5-282 X X X X X 5-283 X X X X X 5-284 X X X X X 5-285 XX X X 5-286 X X X X X 5-287 X X X X X 5-288 X X X X X 5-289 X X X X X5-290 X X X X 5-291 X X X X X 5-292 X X X X X 5-293 X X X X X 5-294 X XX X X 5-295 X X X X 5-296 X X X X X 5-297 X X X X X 5-298 X X X X X5-299 X X X X X 5-300 X X X X 5-301 X X X X X 5-302 X X X X X 5-303 X XX X X 5-304 X X X X X 5-305 X X X X 5-306 X X X X X 5-307 X X X X X5-308 X X X X X 5-309 X X X X X 5-310 X X X X 5-311 X X X X X 5-312 X XX X X 5-313 X X X X X 5-314 X X X X X 5-315 X X X X 5-316 X X X X X5-317 X X X X X 5-318 X X X X X 5-319 X X X X X 5-320 X X X X 5-321 X XX X X 5-322 X X X X X 5-323 X X X X X 5-324 X X X X X 5-325 X X X X5-326 X X X X X 5-327 X X X X X 5-328 X X X X X 5-329 X X X X X 5-330 XX X X 5-331 X X X X X 5-332 X X X X X 5-333 X X X X X 5-334 X X X X X5-335 X X X X 5-336 X X X X X 5-337 X X X X X 5-338 X X X X X 5-339 X XX X X 5-340 X X X X 5-341 X X X X X 5-342 X X X X X 5-343 X X X X X5-344 X X X X X 5-345 X X X X 5-346 X X X X X 5-347 X X X X X 5-348 X XX X X 5-349 X X X X X 5-350 X X X X 5-351 X X X X X 5-352 X X X X X5-353 X X X X X 5-354 X X X X X 5-355 X X X X 5-356 X X X X X 5-357 X XX X X 5-358 X X X X X 5-359 X X X X X 5-360 X X X X 5-361 X X X X X5-362 X X X X X 5-363 X X X X X 5-364 X X X X X 5-365 X X X X 5-366 X XX X X 5-367 X X X X X 5-368 X X X X X 5-369 X X X X X 5-370 X X X X5-371 X X X X X 5-372 X X X X X 5-373 X X X X X 5-374 X X X X X 5-375 XX X X 5-376 X X X X X 5-377 X X X X X 5-378 X X X X X 5-379 X X X X X5-380 X X X X 5-381 X X X X X 5-382 X X X X X 5-383 X X X X X 5-384 X XX X X 5-385 X X X X 5-386 X X X X X 5-387 X X X X X 5-388 X X X X X5-389 X X X X X 5-390 X X X X 5-391 X X X X X 5-392 X X X X X 5-393 X XX X X 5-394 X X X X X 5-395 X X X X 5-396 X X X X X 5-397 X X X X X5-398 X X X X X 5-399 X X X X X 5-400 X X X X 5-401 X X X X X 5-402 X XX X X 5-403 X X X X X 5-404 X X X X X 5-405 X X X X 5-406 X X X X X5-407 X X X X X 5-408 X X X X X 5-409 X X X X X 5-410 X X X X 5-411 X XX X X 5-412 X X X X X 5-413 X X X X X 5-414 X X X X X 5-415 X X X X5-416 X X X X X 5-417 X X X X X 5-418 X X X X X 5-419 X X X X X 5-420 XX X X 5-421 X X X X X 5-422 X X X X X 5-423 X X X X X 5-424 X X X X X5-425 X X X X 5-426 X X X X X 5-427 X X X X X 5-428 X X X X X 5-429 X XX X X 5-430 X X X X 5-431 X X X X X 5-432 X X X X X 5-433 X X X X X5-434 X X X X X 5-435 X X X X 5-436 X X X X X 5-437 X X X X X 5-438 X XX X X 5-439 X X X X X 5-440 X X X X 5-441 X X X X X 5-442 X X X X X5-443 X X X X X 5-444 X X X X X 5-445 X X X X 5-446 X X X X X 5-447 X XX X X 5-448 X X X X X 5-449 X X X X X 5-450 X X X X 5-451 X X X X X5-452 X X X X X 5-453 X X X X X 5-454 X X X X X 5-455 X X X X 5-456 X XX X X 5-457 X X X X X 5-458 X X X X X 5-459 X X X X X 5-460 X X X X5-461 X X X X X 5-462 X X X X X 5-463 X X X X X 5-464 X X X X X 5-465 XX X X 5-466 X X X X X 5-467 X X X X X 5-468 X X X X X 5-469 X X X X X5-470 X X X X 5-471 X X X X X 5-472 X X X X X 5-473 X X X X X 5-474 X XX X X 5-475 X X X X 5-476 X X X X X 5-477 X X X X X 5-478 X X X X X5-479 X X X X X 5-480 X X X X 5-481 X X X X X 5-482 X X X X X 5-483 X XX X X 5-484 X X X X X 5-485 X X X X 5-486 X X X X X 5-487 X X X X X5-488 X X X X X 5-489 X X X X X 5-490 X X X X 5-491 X X X X X 5-492 X XX X X 5-493 X X X X X 5-494 X X X X X 5-495 X X X X 5-496 X X X X X5-497 X X X X X 5-498 X X X X X 5-499 X X X X X 5-500 X X X X 5-501 X XX X X 5-502 X X X X X 5-503 X X X X X 5-504 X X X X X 5-505 X X X X5-506 X X X X X 5-507 X X X X X 5-508 X X X X X 5-509 X X X X X 5-510 XX X X 5-511 X X X X X 5-512 X X X X X 5-513 X X X X X 5-514 X X X X X5-515 X X X X 5-516 X X X X X 5-517 X X X X X 5-518 X X X X X 5-519 X XX X X 5-520 X X X X 5-521 X X X X X 5-522 X X X X X 5-523 X X X X X5-524 X X X X X 5-525 X X X X 5-526 X X X X X 5-527 X X X X X 5-528 X XX X X 5-529 X X X X X 5-530 X X X X 5-531 X X X X X 5-532 X X X X X5-533 X X X X X 5-534 X X X X X 5-535 X X X X 5-536 X X X X X 5-537 X XX X X 5-538 X X X X X 5-539 X X X X X 5-540 X X X X X represents a halogroup (Cl, Br, I or F).

Additional non-limiting examples of compounds of the invention aredescribed in Table 6 along with several biological properties.

TABLE 6 Biological properties of exemplary compounds of the invention. Bcell PI3K δ PI3K γ PI3K α PI3K β proliferation No. Compound IC₅₀ IC₅₀IC₅₀ IC₅₀ EC₅₀ 1

+++ +++ + + ++ 2

+++ +++ + ++ +++ 3

+++ ++ + + ++ 4

+++ +++ + + +++ 5

+++ ++ + + ++ 6

+++ + + + ++ 7

+++ +++ + + ++ 8

+++ +++ + + +++ 9

+++ + + +++ 10

+++ + + ++ 11

+++ +++ 12

+++ +++ 13

+++ +++ 14

++ 15

+++ +++ 16

+++ ++ 17

+++ +++ ++ ++ +++ 18

+ 19

+++ +++ 20

+++ +++ 21

+ 22

+ 23

+++ +++ 24

+++ +++ ++ + +++ 25

++ + + 26

+++ + +++ 27

+ 28

+ 29

++ + + + 30

+++ +++ +++ 31

+++ + ++ 32

+++ ++ +++ 33

++ 34

+++ ++ +++ 35

+ + 36

+ + 37

+ + 38

+++ + + +++ +++ 39

+++ + + + +++ 40

+++ ++ + + +++ 41

+++ ++ 42

+++ +++ 43

+++ + + ++ ++ 44

++ + 45

+++ ++ +++ 46

+++ ++ ++ 47

+++ +++ +++ 48

++ + ++ 49

++ + ++ 50

+++ + + +++ +++ 51

+ 52

+++ ++ ++ ++ +++ 53

++ + 54

+++ ++ + + +++ 55

+++ ++ + + +++ 56

+++ +++ + + +++ 57

+++ +++ ++ ++ +++ 58

++ ++ 59

+++ ++ + + +++ 60

+ + + 61

+++ +++ +++ 62

++ ++ 63

+++ ++ + + +++ 64

+++ ++ + + +++ 65

+++ +++ ++ ++ 66

+++ +++ + ++ 67

+ + + + 68

+++ ++ + ++ +++ 69

+++ + + + +++ 70

+++ ++ ++ +++ +++ 71

+++ + + + ++ 72

+++ + + ++ +++ 73

+++ + + +++ +++ 74

+++ + + ++ +++ 75

+++ + + + +++ 76

+ + + + 77

+++ + + + +++ 78

+++ + + + ++ 79

+++ +++ +++ + +++ 80

+++ +++ +++ +++ +++ 81

+++ + + + ++ 82

+++ + + + +++ 83

+++ +++ + + +++ 84

+++ +++ + + +++ 85

+++ +++ ++ + +++ 86

+++ +++ + + ++ 87

+ + + + 88

++ + + + 89

++ + + + 90

++ + + + 91

++ ++ + + 92

+++ +++ + + +++ 93

+++ ++ + + 94

+++ +++ + + ++ 95

+++ + + + 96

+++ ++ + + 97

+++ ++ + ++ 98

+++ +++ + + 99

+++ +++ ++ ++ 100

+ 101

++ + + + ++ 102

+ 103

+ + 104

+++ ++ + + +++ 105

+++ ++ + + ++ 106

++ + 107

+++ + + + +++ 108

++ + + + 109

++ + + + 110

++ + + + 111

++ + + + 112

+++ ++ + + 113

+++ + + + 114

+++ + + + 115

++ + + + 116

++ + + + 117

+++ + + + 118

+++ ++ + + 119

+++ +++ ++ + 120

+ 121

+ 122

+ 123

+ 124

+ 125

+ 126

+ 127

+++ + ++ 128

+++ +++ +++ +++ 129

+++ +++ +++ ++ +++ 130

+++ +++ +++ +++ +++ 131

+++ +++ ++ + ++ 132

+++ +++ +++ ++ +++ 133

+++ +++ + + ++ 134

+++ +++ + + ++ 135

+++ +++ ++ + +++ 136

+++ +++ + + ++ 137

+++ +++ + + ++ 138

+++ +++ + + ++ 139

+++ +++ +++ +++ +++ 140

+++ +++ +++ ++ +++ 141

+++ +++ ++ + +++ 142

+++ +++ ++ + +++ 143

+++ +++ ++ + +++ 144

+++ +++ ++ + +++ 145

+++ +++ + + +++ 146

+++ +++ + + ++ 147

+++ +++ ++ ++ 148

+++ +++ + +++ 149

+++ +++ + +++ 150

+++ +++ + +++ 151

+++ +++ ++ +++ 152

+++ +++ ++ + ++ 153

+++ +++ +++ ++ ++ 154

+++ ++ +++ +++ 155

+++ + + ++ 156

+++ ++ + + ++ 157

++ + + + + 158

+ + + + + 159

+++ +++ ++ + + 160

++ + + 161

+ + 162

+ + 163

++ +++ 164

+++ +++ 165

+++ + + ++ +++ 166

+++ ++ ++ + +++ 167

+++ +++ +++ ++ +++ 168

+++ + + ++ +++ 169

+++ ++ ++ ++ +++ 170

+++ ++ + + 171

+++ +++ ++ + +++ 172

+ + + 173

+ + + 174

+++ + +++ +++ 175

+++ ++ + +++ 176

+++ ++ + +++ 177

+ + + 178

+ + + 179

++ + + + ++ 180

+++ ++ + + ++ 181

+++ +++ + + ++ 182

+++ +++ + ++ 183

++ ++ + 184

+++ +++ + + ++ 185

+++ + + ++ +++ 186

+++ ++ + +++ 187

+++ +++ ++ +++ 188

+ + + 189

+ + + 190

+ + + + 191

++ + + + 192

+++ +++ + + ++ 193

+ + + + 194

++ + + + 195

+++ +++ +++ + +++ 196

+++ +++ ++ + ++ 197

+++ + + ++ +++ 198

+++ ++ ++ +++ +++ 199

+++ +++ ++ +++ +++ 200

+++ + + ++ The measured activityof the compounds of the invention (EC50or IC50) is denoted as “+++” if less or equal to 100 nM, “++” if greaterthan 100 nM but less than or equal to 1 μM, and “+” if greater than 1μM.

Additional compounds of the invention are described below:

Preparation of the Compounds of the Invention

Compounds of the invention may be synthesized by the general syntheticSchemes 1 and 2 illustrated below. In general synthetic scheme 1, anaromatic group comprising two reactive groups X and Y is first coupledto the R⁹ group via the reactive group X. The introduction of the linkerL and the heteroaromatic moiety Z is performed in a subsequent step. Ingeneral scheme 2, the linker L and heteroaromatic moiety Z are firstcoupled to the aromatic group comprising two reactive groups X and Y.The coupling step to introduce the R⁹ moiety is performed subsequently.

Various reagents may be used to perform the coupling reactions necessaryto introduce the R⁹, L and Z moieties. X and Y are reactive groups whichcan react with precursors of R⁹ and L or Z moieties. Alternatively, Xand Y are latent or protected reaction groups which are converted toreactive groups during or prior to the coupling reactions. Variouscoupling reactions may be suitable for this purpose. Some known types ofcoupling reactions which can involve aromatic ring compounds include theHeck reactions and Suzuki reactions. Such reactions are described, forexample, in N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2457-2483.

For example, X may be a halogen atom. If R⁹ comprises a primary orsecondary amino group, it may be attached to the aryl group via anamination reaction. Such a reaction may be performed in the presence ofa base and/or a catalyst such as a palladium catalyst. In otherembodiments, X is a halogen atom and R⁹ is an aryl group. A coupling maybe effected between X and a precursor compound of R⁹, such as a boronicacid (Suzuki coupling) or stannane precursor (Stille coupling).

The synthesis of several compounds of the invention is illustrated inSynthetic Schemes 3-15. The general synthetic strategy employed in theseschemes is believed to be widely applicable to synthesize the compoundsof the invention, and the specific compounds and reagents describe servemerely to exemplify the general synthetic approaches disclosed herein.Scheme 3 shows the preparation of a compound of the invention byreduction of a starting aldehyde 3a to an alcohol in step 1. Such areaction may be performed, for example, by sodium borohydride reductionin methanol. In step 2, compound 3b is coupled to pyrrolidine in thepresence of a solvent such as 1,4-dioxane. The alcohol 3c is convertedto a reactive halide in step 3 by reaction with a reagent such asCBr₄/PPh₃ in a solvent such as dichloromethane. A heterocyclic moietysuch as a pyrazolopyrimide (e.g.3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine) may be coupled to the halide3d (e.g. in a base such as potassium carbonate and a solvent such asdimethylformamide) to form the compound 3e in step 4. In step 5, thepyrazolopyrimidine subunit is further derivatized via a reaction such asa Suzuki coupling (e.g. using Pd(PPh₃)₄ as a catalyst) to yield compound3f.

Scheme 4 shows an alternative synthesis of the compound 3f. In Step 1, astarting aldehyde 3a is reduced to an alcohol. Such a reaction may beperformed, for example, by sodium borohydride reduction in methanol. InStep 2, compound 3b is converted to a reactive halide 4a by reactionwith a reagent such as CBr₄/PPh₃ in a solvent such as dichloromethane.Coupling to a heterocyclic moiety such as a pyrazolopyrimide (e.g.3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine) is performed in step 3, forexample in a base such as potassium carbonate and a solvent such asdimethylformamide) to yield compound 4b. Compound 4b is then coupled topyrrolidine in Step 4 in the presence of a solvent such as 1,4-dioxaneto produce compound 3e. In step 5, compound 3e is further derivatizedvia a reaction such as a Suzuki coupling (e.g. using Pd(PPh₃)₄ as acatalyst) to yield compound 3f.

Scheme 5 shows an additional alternative synthesis of the compound 3f.In step 1, a starting aldehyde 3a is reduced to an alcohol. Such areaction may be performed, for example, by sodium borohydride reductionin methanol. In step 2, compound 3b is converted to a reactive halide 4bby reaction with a reagent such as CBr₄/PPh₃ in a solvent such asdichloromethane. Coupling to a heterocyclic moiety such as a derivatizedpyrazolopyrimide (e.g.3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine) isperformed in step 3, for example in a base such as potassium t-butoxideand a solvent such as dimethylformamide) to yield compound 5a. Ifnecessary, the resulting compound 5a is deprotected, for example byremoval of a methoxy group by a reagent such as BBr₃ in dichloromethane.The resulting compound 5b is then coupled to pyrrolidine in the presenceof a solvent such as 1,4-dioxane to yield compound 3f.

Scheme 6 shows the preparation of a compound of the invention byreduction of a starting aldehyde 6a to an alcohol in step 1. Such areaction may be performed, for example, by sodium borohydride reductionin methanol. In step 2, compound 6b is coupled to an aryl group via, forexample, a Suzuki coupling. In the example shown, o-tolylboronic acid isreacted with 6b in the presence of Pd(PPh₃)₄, a base such as Na₂CO₃ anda solvent such as DMF. The resulting alcohol 6c is converted to areactive halide in step 3 by reaction with a reagent such as CBr₄/PPh₃in a solvent such as dichloromethane. A heterocyclic moiety such as apyrazolopyrimide (e.g. 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine) maybe coupled to the halide 6d (e.g. in a base such as potassium carbonateand a solvent such as dimethylformamide) to form the compound 6e in step4. In step 5, the pyrazolopyrimidine subunit is further derivatized viaa reaction such as a Suzuki coupling (e.g. using Pd(PPh₃)₄ as acatalyst) to yield compound 6f.

Scheme 7 shows an alternative synthesis of the compound 6f. In step 1, astarting aldehyde 6a is reduced to an alcohol. Such a reaction may beperformed, for example, by sodium borohydride reduction in methanol. Instep 2, compound 6b is converted to a reactive halide 7a by reactionwith a reagent such as CBr₄/PPh₃ in a solvent such as dichloromethane.Coupling to a heterocyclic moiety such as a derivatized pyrazolopyrimide(e.g. 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine)is performed in step 3, for example in a base such as potassiumt-butoxide and a solvent such as dimethylformamide). The resultingcompound 7b is then coupled to an aryl group via, for example, a Suzukicoupling. In the example shown, o-tolylboronic acid is reacted with 7bin the presence of Pd(PPh₃)₄, a base such as Na₂CO₃ and a solvent suchas DMF. If necessary, the resulting compound 7c is deprotected, forexample by removal of a methoxy group by a reagent such as BBr₃ indichloromethane to yield compound 6f.

Scheme 8 shows the preparation of a compound of the invention byreduction of a starting acid 8a to an alcohol in step 1. Such a reactionmay be performed, for example, by LiAlH₄ reduction in methanol. In step2, compound 8b is coupled to an aryl group via, for example, a Suzukicoupling. In the example shown, 2-fluorophenylboronic acid is reactedwith 8b in the presence of Pd(PPh₃)₄, a base such as Na₂CO₃ and asolvent such as DME-water. The resulting alcohol 8c is converted to areactive halide in step 3 by reaction with a reagent such as CBr₄/PPh₃in a solvent such as dichloromethane. A heterocyclic moiety such as apyrazolopyrimide (e.g. 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine) maybe coupled to the halide 8d (e.g. in a base such as potassium carbonateand a solvent such as dimethylformamide) to form the compound 8e in step4. In step 5, the pyrazolopyrimidine subunit is further derivatized viaa reaction such as a Suzuki coupling (e.g. using Pd(PPh₃)₄ as acatalyst) to yield compound 8f.

Scheme 9 shows the preparation of a compound of the invention byreduction of a starting aldehyde 9a to an alcohol in step 1. Such areaction may be performed, for example, by sodium borohydride reductionin methanol. In step 2, compound 9b is coupled to pyrrolidine in thepresence of a solvent such as 1,4-dioxane. The resulting alcohol 9c isconverted to a reactive halide in step 3 by reaction with a reagent suchas CBr₄/PPh₃ in a solvent such as acetonitrile. A heterocyclic moietysuch as a pyrazolopyrimide (e.g.3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine) may be coupled to the halide9d (e.g. in a base such as potassium carbonate and a solvent such asdimethylformamide) to form the compound 9e in step 4. In step 5, thepyrazolopyrimidine subunit is further derivatized via a reaction such asa Suzuki coupling (e.g. using Pd(PPh₃)₄ as a catalyst) with3-fluoro-5-hydroxyphenylboronic acid to yield compound 9f.

Scheme 10 illustrates a synthesis of the compound 10f. In step 1, astarting aldehyde 10a is converted to an alcohol, for example, byGrignard addition of an alkylmagnesium halide reagent. In step 2,compound 10b is converted to a reactive halide by reaction with areagent such as CBr₄/PPh₃ in a solvent such as acetonitrile. Coupling toa heterocyclic moiety such as a pyrazolopyrimide (e.g.3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine) is performed in step 3, forexample in a base such as potassium t-butoxide and a solvent such asdimethylformamide). The resulting compound 10d is then coupled topyrrolidine in the presence of a solvent such as 1,4-dioxane. In step 5,the pyrazolopyrimidine subunit is further derivatized via a reactionsuch as a Suzuki coupling (e.g. using Pd(PPh₃)₄ as a catalyst) to yieldcompound 10f.

Scheme 11 exemplifies a synthesis of the compound 11f. In step 1, astarting aldehyde 11a is converted to an alcohol, for example, byGrignard addition of an alkylmagnesium halide reagent. In step 2,compound 11b is coupled to an aryl group via, for example, a Suzukicoupling using phenylboronic acid in the presence of Pd(OAc)₂, a basesuch as Na₂CO₃ and a solvent such as ethanol/DMF/water. The resultingcompounds 11c is converted to a reactive halide by reaction with areagent such as CBr₄/PPh₃ in a solvent such as acetonitrile. Coupling toa heterocyclic moiety such as a pyrazolopyrimide (e.g.3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine) is performed in step 3, forexample in a base such as potassium t-butoxide and a solvent such asdimethylformamide. In step 5, the resulting compound lid is furtherderivatized via a reaction such as a Suzuki coupling (e.g. usingPd(PPh₃)₄ as a catalyst) to yield compound 11f.

Scheme 12 shows a synthesis of the compound 12e. In step 1, a startingaldehyde 12a is converted to an alcohol, for example, by Grignardaddition of an alkylmagnesium halide reagent. In step 2, compound 12b isconverted to a reactive halide by reaction with a reagent such asCBr₄/PPh₃ in a solvent such as acetonitrile. Subsequent reaction with aheterocyclic compound such as 9H-purin-6-amine leads to formation of theintermediate 12d. This intermediate is then coupled to an aryl groupvia, for example, a Suzuki coupling using phenylboronic acid in thepresence of Pd(OAc)₂, a base such as Na₂CO₃ and a solvent such asethanol/DMF/water. Alternatively, compound 12d is reacted withpyrrolidine in the presence of a solvent such as 1,4-dioxane, leading toformation of product 12f.

Scheme 13 describes the synthesis of additional compounds comprisingheteroaromatic residues. The starting material is the intermediate 12cprepared as described above. Coupling with a derivatized bicyclicheteroaromatic residue (in the example shown,9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine) results in compound 13b,which is further reacted with a group such as pyrrolidine (shown) toyield compounds 13c. Deprotection of the purine moiety in HCl/ethanolresults in compound 13d.

A synthetic route to quinoxaline compounds of the invention isillustrated in Scheme 14. Quinoxaline 14b is prepared by cyclization ofcompound 14a with a reagent such as ethyl 3-bromo-2-oxopropanoate.Conversion to the halide 14c is performed using a reagent such asphosphorus oxychloride or similar reagents. Steps 3, 4 and 5 follow thecorresponding steps in Scheme 10, yielding compound 14f.

Scheme 15 describes the synthesis of compounds such as 15g. Intermediate15d is prepared as described for compound 4b. Treatment with NaOH in asolvent such as 1,4-dioxane at 80 C yields 15e, which is furtheralkylated using a reagent such as methyl iodide in potassiumt-butoxide/DMF to yield 15f. Compound 15g is obtained following Suzukicoupling as described above.

A synthetic route to additional quinoxaline compounds of the inventionis illustrated in Scheme 16. Quinoxaline 16b is prepared by cyclizationof compound 16a with a reagent such as ethyl 3-bromo-2-oxopropanoate inethanol. Reaction with Boc anhydride in DMAP/CH₂C₂ leads to theprotected intermediate 16c. Coupling to a heterocyclic moiety such as apyrazolopyrimide is performed in step 3. Deprotection and alkylation,e.g. using methyl iodide, results in compound 16g.

In some embodiments, one or more subject compounds bind specifically toa P13 kinase or a protein kinase selected from the group consisting ofmTor, DNA-dependent protein kinase DNA-dependent protein kinase (Pubmedprotein accession number (PPAN) AAA79184), Abl tyrosine kinase(CAA52387), Bcr-Abl, hemopoietic cell kinase (PPAN CA119695), Src (PPANCAA24495), vascular endothelial growth factor receptor 2 (PPANABB82619), vascular endothelial growth factor receptor-2 (PPANABB82619), epidermal growth factor receptor (PPAN AG43241), EPH receptorB4 (PPAN EAL23820), stem cell factor receptor (PPAN AAF22141),Tyrosine-protein kinase receptor TIE-2 (PPAN Q02858), fms-relatedtyrosine kinase 3 (PPAN NP_004110), platelet-derived growth factorreceptor alpha (PPAN NP_990080), RET (PPAN CAA73131), and any otherprotein kinases listed in the appended tables and figures, as well asany functional mutants thereof. In some embodiments, the IC50 of asubject compound for p110α, p110β, p110γ, or p110δ is less than about 1uM, less than about 100 nM, less than about 50 nM, less than about 10nM, less than 1 nM or even less than about 0.5 nM. In some embodiments,the IC50 of a subject compound for mTor is less than about 1 uM, lessthan about 100 nM, less than about 50 nM, less than about 10 nM, lessthan 1 nM or even less than about 0.5 nM. In some other embodiments, oneor more subject compounds exhibit dual binding specificity and arecapable of inhibiting a PI3 kinase (e.g., a class I P13 kinease) as wellas a protein kinase (e.g., mTor) with an IC50 value less than about 1uM, less than about 100 nM, less than about 50 nM, less than about 10nM, less than 1 nM or even less than about 0.5 nM. One or more subjectcompounds are capable of inhibiting tyrosine kinases including, forexample, DNA-dependent protein kinase DNA-dependent protein kinase(Pubmed protein accession number (PPAN) AAA79184), Abl tyrosine kinase(CAA52387), Bcr-Abl, hemopoietic cell kinase (PPAN CAI19695), Src (PPANCAA24495), vascular endothelial growth factor receptor 2 (PPANABB82619), vascular endothelial growth factor receptor-2 (PPANABB82619), epidermal growth factor receptor (PPAN AG43241), EPH receptorB4 (PPAN EAL23820), stem cell factor receptor (PPAN AAF22141),Tyrosine-protein kinase receptor TIE-2 (PPAN Q02858), fms-relatedtyrosine kinase β (PPAN NP_004110), platelet-derived growth factorreceptor alpha (PPAN NP_990080), RET (PPAN CAA73131), and functionalmutants thereof. In some embodiments, the tyrosine kinase is Abl,Bcr-Abl, EGFR, or Flt-3, and any other kinases listed in the Tablesherein.

In some embodiments, the compounds of the present invention exhibits oneor more functional characteristics disclosed herein. For example, one ormore subject compounds bind specifically to a PI3 kinase. In someembodiments, the IC50 of a subject compound for p110α, p110β, p110γ, orp110δ is less than about 1 uM, less than about 100 nM, less than about50 nM, less than about 10 nM, less than about 1 nM, less than about 0.5nM, less than about 100 μM, or less than about 50 μM.

In some embodiments, one or more of the subject compounds mayselectively inhibit one or more members of type I or class Iphosphatidylinositol 3-kinases (PI3-kinase) with an IC50 value of about100 nM, 50 nM, 10 nM, 5 nM, 100 μM, 10 μM or 1 μM, or less as measuredin an in vitro kinase assay.

In some embodiments, one or more of the subject compound may selectivelyinhibit one or two members of type I or class I phosphatidylinositol3-kinases (PI3-kinase) consisting of PI3-kinase α, PI3-kinase β,PI3-kinase γ, and PI3-kinase δ. In some aspects, some of the subjectcompounds selectively inhibit PI3-kinase δ as compared to all other typeI PI3-kinases. In other aspects, some of the subject compoundsselectively inhibit PI3-kinase δ and PI3-kinase γ as compared to therest of the type I PI3-kinases. In yet other aspects, some of thesubject compounds selectively inhibit PI3-kinase α and PI3-kinase β ascompared to the rest of the type I PI3-kinases. In still yet some otheraspects, some of the subject compounds selectively inhibit PI3-kinase δand PI3-kinase α as compared to the rest of the type I PI3-kinases. Instill yet some other aspects, some of the subject compounds selectivelyinhibit PI3-kinase δ and PI3-kinase β as compared to the rest of thetype I PI3-kinases, or selectively inhibit PI3-kinase δ and PI3-kinase αas compared to the rest of the type I PI3-kinases, or selectivelyinhibit PI3-kinase α and PI3-kinase γ as compared to the rest of thetype I PI3-kinases, or selectively inhibit PI3-kinase γ and PI3-kinase βas compared to the rest of the type I PI3-kinases.

In yet another aspect, an inhibitor that selectively inhibits one ormore members of type I PI3-kinases, or an inhibitor that selectivelyinhibits one or more type I PI3-kinase mediated signaling pathways,alternatively can be understood to refer to a compound that exhibits a50% inhibitory concentration (IC50) with respect to a given type IPI3-kinase, that is at least at least 10-fold, at least 20-fold, atleast 50-fold, at least 100-fold, at least 1000-fold, at least10,100-fold, or lower, than the inhibitor's IC50 with respect to therest of the other type I PI3-kinases.

The invention provides pharmaceutical compositions comprising one ormore compounds of the present invention. In some embodiments, theinvention provides pharmaceutical compositions for treating diseases orconditions related to an undesirable, over-active, harmful ordeleterious immune response in a mammal. Such undesirable immuneresponse can be associated with or result in, e.g., asthma, emphysema,bronchitis, psoriasis, allergy, anaphylaxsis, auto-immune diseases,rhuematoid arthritis, graft versus host disease, and lupuserythematosus. The pharmaceutical compositions of the present inventioncan be used to treat other respiratory diseases including but notlimited to diseases affecting the lobes of lung, pleural cavity,bronchial tubes, trachea, upper respiratory tract, or the nerves andmuscle for breathing.

In some embodiments, the invention provides pharmaceutical compositionsfor the treatment of disorders such as hyperproliferative disorderincluding but not limited to cancer such as acute myeloid leukemia,thymus, brain, lung, squamous cell, skin, eye, retinoblastoma,intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric,stomach, pancreatic, bladder, breast, cervical, head, neck, renal,kidney, liver, ovarian, prostate, colorectal, esophageal, testicular,gynecological, thyroid, CNS, PNS, AIDS related AIDS-Related (e.g.

Lymphoma and Kaposi's Sarcoma) or Viral-Induced cancer. In someembodiments, said pharmaceutical composition is for the treatment of anon-cancerous hyperproliferative disorder such as benign hyperplasia ofthe skin (e. g., psoriasis), restenosis, or prostate (e. g., benignprostatic hypertrophy (BPH)).

The invention also provides compositions for the treatment of liverdiseases (including diabetes), pancreatitis or kidney disease (includingproliferative glomerulonephritis and diabetes-induced renal disease) orpain in a mammal.

The invention further provides a composition for the prevention ofblastocyte implantation in a mammal.

The invention also relates to a composition for treating a diseaserelated to vasculogenesis or angiogenesis in a mammal which can manifestas tumor angiogenesis, chronic inflammatory disease such as rheumatoidarthritis, inflammatory bowel disease, atherosclerosis, skin diseasessuch as psoriasis, eczema, and scleroderma, diabetes, diabeticretinopathy, retinopathy of prematurity, age-related maculardegeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

The subject pharmaceutical compositions are typically formulated toprovide a therapeutically effective amount of a compound of the presentinvention as the active ingredient, or a pharmaceutically acceptablesalt, ester, prodrug, solvate, hydrate or derivative thereof. Wheredesired, the pharmaceutical compositions contain pharmaceuticallyacceptable salt and/or coordination complex thereof, and one or morepharmaceutically acceptable excipients, carriers, including inert soliddiluents and fillers, diluents, including sterile aqueous solution andvarious organic solvents, permeation enhancers, solubilizers andadjuvants.

The subject pharmaceutical compositions can be administered alone or incombination with one or more other agents, which are also typicallyadministered in the form of pharmaceutical compositions. Where desired,the subject compounds and other agent(s) may be mixed into a preparationor both components may be formulated into separate preparations to usethem in combination separately or at the same time.

In some embodiments, the concentration of one or more of the compoundsprovided in the pharmaceutical compositions of the present invention isless than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%,16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%,0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%,0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%,0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%,0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.

In some embodiments, the concentration of one or more of the compoundsof the present invention is greater than 90%, 80%, 70%, 60%, 50%, 40%,30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%,17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%,15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%,12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%,10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%,7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%,4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%,1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%,0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%,0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%,0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w,w/v, or v/v.

In some embodiments, the concentration of one or more of the compoundsof the present invention is in the range from approximately 0.0001% toapproximately 50%, approximately 0.001% to approximately 40%,approximately 0.01% to approximately 30%, approximately 0.02% toapproximately 29%, approximately 0.03% to approximately 28%,approximately 0.04% to approximately 27%, approximately 0.05% toapproximately 26%, approximately 0.06% to approximately 25%,approximately 0.07% to approximately 24%, approximately 0.08% toapproximately 23%, approximately 0.09% to approximately 22%,approximately 0.1% to approximately 21%, approximately 0.2% toapproximately 20%, approximately 0.3% to approximately 19%,approximately 0.4% to approximately 18%, approximately 0.5% toapproximately 17%, approximately 0.6% to approximately 16%,approximately 0.7% to approximately 15%, approximately 0.8% toapproximately 14%, approximately 0.9% to approximately 12%,approximately 1% to approximately 10% w/w, w/v or v/v. v/v.

In some embodiments, the concentration of one or more of the compoundsof the present invention is in the range from approximately 0.001% toapproximately 10%, approximately 0.01% to approximately 5%,approximately 0.02% to approximately 4.5%, approximately 0.03% toapproximately 4%, approximately 0.04% to approximately 3.5%,approximately 0.05% to approximately 3%, approximately 0.06% toapproximately 2.5%, approximately 0.07% to approximately 2%,approximately 0.08% to approximately 1.5%, approximately 0.09% toapproximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v orv/v.

In some embodiments, the amount of one or more of the compounds of thepresent invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g,8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g,3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g,0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g,0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g,0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

In some embodiments, the amount of one or more of the compounds of thepresent invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g,0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g,0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g,0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g,0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g,0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g,0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5g, 6 g, 6.5g, 7 g, 7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

In some embodiments, the amount of one or more of the compounds of thepresent invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g,0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

The compounds according to the invention are effective over a widedosage range. For example, in the treatment of adult humans, dosagesfrom 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, andfrom 5 to 40 mg per day are examples of dosages that may be used. Anexemplary dosage is 10 to 30 mg per day. The exact dosage will dependupon the route of administration, the form in which the compound isadministered, the subject to be treated, the body weight of the subjectto be treated, and the preference and experience of the attendingphysician.

Described below are non-limiting exemplary pharmaceutical compositionsand methods for preparing the same.

Pharmaceutical compositions for oral administration. In someembodiments, the invention provides a pharmaceutical composition fororal administration containing a compound of the present invention, anda pharmaceutical excipient suitable for oral administration.

In some embodiments, the invention provides a solid pharmaceuticalcomposition for oral administration containing: (i) an effective amountof a compound of the present invention; optionally (ii) an effectiveamount of a second agent; and (iii) a pharmaceutical excipient suitablefor oral administration. In some embodiments, the composition furthercontains: (iv) an effective amount of a third agent.

In some embodiments, the pharmaceutical composition may be a liquidpharmaceutical composition suitable for oral consumption. Pharmaceuticalcompositions of the invention suitable for oral administration can bepresented as discrete dosage forms, such as capsules, cachets, ortablets, or liquids or aerosol sprays each containing a predeterminedamount of an active ingredient as a powder or in granules, a solution,or a suspension in an aqueous or non-aqueous liquid, an oil-in-wateremulsion, or a water-in-oil liquid emulsion. Such dosage forms can beprepared by any of the methods of pharmacy, but all methods include thestep of bringing the active ingredient into association with thecarrier, which constitutes one or more necessary ingredients. Ingeneral, the compositions are prepared by uniformly and intimatelyadmixing the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product intothe desired presentation. For example, a tablet can be prepared bycompression or molding, optionally with one or more accessoryingredients. Compressed tablets can be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such aspowder or granules, optionally mixed with an excipient such as, but notlimited to, a binder, a lubricant, an inert diluent, and/or a surfaceactive or dispersing agent. Molded tablets can be made by molding in asuitable machine a mixture of the powdered compound moistened with aninert liquid diluent.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising an active ingredient, since water canfacilitate the degradation of some compounds. For example, water may beadded (e.g., 5%) in the pharmaceutical arts as a means of simulatinglong-term storage in order to determine characteristics such asshelf-life or the stability of formulations over time. Anhydrouspharmaceutical compositions and dosage forms of the invention can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. Pharmaceutical compositions anddosage forms of the invention which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition may be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous compositions maybe packaged using materials known to prevent exposure to water such thatthey can be included in suitable formulary kits. Examples of suitablepackaging include, but are not limited to, hermetically sealed foils,plastic or the like, unit dose containers, blister packs, and strippacks.

An active ingredient can be combined in an intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier can take a wide variety of formsdepending on the form of preparation desired for administration. Inpreparing the compositions for an oral dosage form, any of the usualpharmaceutical media can be employed as carriers, such as, for example,water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents, and the like in the case of oral liquid preparations(such as suspensions, solutions, and elixirs) or aerosols; or carrierssuch as starches, sugars, micro-crystalline cellulose, diluents,granulating agents, lubricants, binders, and disintegrating agents canbe used in the case of oral solid preparations, in some embodimentswithout employing the use of lactose. For example, suitable carriersinclude powders, capsules, and tablets, with the solid oralpreparations. If desired, tablets can be coated by standard aqueous ornonaqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixturesthereof.

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants may be used in the compositions of the invention toprovide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant may produce tablets which maydisintegrate in the bottle. Too little may be insufficient fordisintegration to occur and may thus alter the rate and extent ofrelease of the active ingredient(s) from the dosage form. Thus, asufficient amount of disintegrant that is neither too little nor toomuch to detrimentally alter the release of the active ingredient(s) maybe used to form the dosage forms of the compounds disclosed herein. Theamount of disintegrant used may vary based upon the type of formulationand mode of administration, and may be readily discernible to those ofordinary skill in the art. About 0.5 to about 15 weight percent ofdisintegrant, or about 1 to about 5 weight percent of disintegrant, maybe used in the pharmaceutical composition. Disintegrants that can beused to form pharmaceutical compositions and dosage forms of theinvention include, but are not limited to, agar-agar, alginic acid,calcium carbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oraladministration, the essential active ingredient therein may be combinedwith various sweetening or flavoring agents, coloring matter or dyesand, if so desired, emulsifying and/or suspending agents, together withsuch diluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

The tablets can be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin or olive oil.

Surfactant which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to,hydrophilic surfactants, lipophilic surfactants, and mixtures thereof.That is, a mixture of hydrophilic surfactants may be employed, a mixtureof lipophilic surfactants may be employed, or a mixture of at least onehydrophilic surfactant and at least one lipophilic surfactant may beemployed.

A suitable hydrophilic surfactant may generally have an HLB value of atleast 10, while suitable lipophilic surfactants may generally have anHLB value of or less than about 10. An empirical parameter used tocharacterize the relative hydrophilicity and hydrophobicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions. Hydrophilic surfactants are generally considered tobe those compounds having an HLB value greater than about 10, as well asanionic, cationic, or zwitterionic compounds for which the HLB scale isnot generally applicable. Similarly, lipophilic (i.e., hydrophobic)surfactants are compounds having an HLB value equal to or less thanabout 10. However, HLB value of a surfactant is merely a rough guidegenerally used to enable formulation of industrial, pharmaceutical andcosmetic emulsions.

Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts;fusidic acid salts; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; lecithins and hydrogenated lecithins;lysolecithins and hydrogenated lysolecithins; phospholipids andderivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acylactylates; mono- and di-acetylated tartaricacid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof.

Within the aforementioned group, ionic surfactants include, by way ofexample: lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts; salts ofalkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures thereof.

Ionic surfactants may be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants may include, but not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylenesterols, derivatives, and analogues thereof; polyoxyethylated vitaminsand derivatives thereof; polyoxyethylene-polyoxypropylene blockcopolymers; and mixtures thereof; polyethylene glycol sorbitan fattyacid esters and hydrophilic transesterification products of a polyolwith at least one member of the group consisting of triglycerides,vegetable oils, and hydrogenated vegetable oils. The polyol may beglycerol, ethylene glycol, polyethylene glycol, sorbitol, propyleneglycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol,polyglyceryl-10oleate, Tween 40, Tween 60, sucrose monostearate, sucrosemonolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG15-100 octyl phenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids and sterols; oil-solublevitamins/vitamin derivatives; and mixtures thereof. Within this group,preferred lipophilic surfactants include glycerol fatty acid esters,propylene glycol fatty acid esters, and mixtures thereof, or arehydrophobic transesterification products of a polyol with at least onemember of the group consisting of vegetable oils, hydrogenated vegetableoils, and triglycerides.

In one embodiment, the composition may include a solubilizer to ensuregood solubilization and/or dissolution of the compound of the presentinvention and to minimize precipitation of the compound of the presentinvention. This can be especially important for compositions fornon-oral use, e.g., compositions for injection.

A solubilizer may also be added to increase the solubility of thehydrophilic drug and/or other components, such as surfactants, or tomaintain the composition as a stable or homogeneous solution ordispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, .epsilon.-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactoneand isomers thereof, β-butyrolactone and isomers thereof; and othersolubilizers known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, and water.

Mixtures of solubilizers may also be used. Examples include, but notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. Particularlypreferred solubilizers include sorbitol, glycerol, triacetin, ethylalcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included is not particularlylimited. The amount of a given solubilizer may be limited to abioacceptable amount, which may be readily determined by one of skill inthe art. In some circumstances, it may be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the composition to a patientusing conventional techniques, such as distillation or evaporation.Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%,50%, 100%, or up to about 200% by weight, based on the combined weightof the drug, and other excipients. If desired, very small amounts ofsolubilizer may also be used, such as 5%, 2%, 1% or even less.Typically, the solubilizer may be present in an amount of about 1% toabout 100%, more typically about 5% to about 25% by weight.

The composition can further include one or more pharmaceuticallyacceptable additives and excipients. Such additives and excipientsinclude, without limitation, detackifiers, anti-foaming agents,buffering agents, polymers, antioxidants, preservatives, chelatingagents, viscomodulators, tonicifiers, flavorants, colorants, odorants,opacifiers, suspending agents, binders, fillers, plasticizers,lubricants, and mixtures thereof.

In addition, an acid or a base may be incorporated into the compositionto facilitate processing, to enhance stability, or for other reasons.Examples of pharmaceutically acceptable bases include amino acids, aminoacid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide,sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate,magnesium hydroxide, magnesium aluminum silicate, synthetic aluminumsilicate, synthetic hydrocalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, trimethylamine,tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable arebases that are salts of a pharmaceutically acceptable acid, such asacetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, amino acids, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, fatty acids, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionicacid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinicacid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonicacid, uric acid, and the like. Salts of polyprotic acids, such as sodiumphosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphatecan also be used.

When the base is a salt, the cation can be any convenient andpharmaceutically acceptable cation, such as ammonium, alkali metals,alkaline earth metals, and the like. Example may include, but notlimited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid, uric acid and the like.

Pharmaceutical compositions for injection. In some embodiments, theinvention provides a pharmaceutical composition for injection containinga compound of the present invention and a pharmaceutical excipientsuitable for injection. Components and amounts of agents in thecompositions are as described herein. The forms in which the novelcompositions of the present invention may be incorporated foradministration by injection include aqueous or oil suspensions, oremulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, aswell as elixirs, mannitol, dextrose, or a sterile aqueous solution, andsimilar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils may also be employed. The proper fluidity can bemaintained, for example, by the use of a coating, such as lecithin, forthe maintenance of the required particle size in the case of dispersionand by the use of surfactants.

The prevention of the action of microorganisms can be brought about byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the compoundof the present invention in the required amount in the appropriatesolvent with various other ingredients as enumerated above, as required,followed by filtered sterilization. Generally, dispersions are preparedby incorporating the various sterilized active ingredients into asterile vehicle which contains the basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions,certain desirable methods of preparation are vacuum-drying andfreeze-drying techniques which yield a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Pharmaceutical compositions for topical (e.g., transdermal) delivery. Insome embodiments, the invention provides a pharmaceutical compositionfor transdermal delivery containing a compound of the present inventionand a pharmaceutical excipient suitable for transdermal delivery.

Compositions of the present invention can be formulated intopreparations in solid, semi-solid, or liquid forms suitable for local ortopical administration, such as gels, water soluble jellies, creams,lotions, suspensions, foams, powders, slurries, ointments, solutions,oils, pastes, suppositories, sprays, emulsions, saline solutions,dimethylsulfoxide (DMSO)-based solutions. In general, carriers withhigher densities are capable of providing an area with a prolongedexposure to the active ingredients. In contrast, a solution formulationmay provide more immediate exposure of the active ingredient to thechosen area.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients, which are compounds that allow increasedpenetration of, or assist in the delivery of, therapeutic moleculesacross the stratum corneum permeability barrier of the skin. There aremany of these penetration-enhancing molecules known to those trained inthe art of topical formulation. Examples of such carriers and excipientsinclude, but are not limited to, humectants (e.g., urea), glycols (e.g.,propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleicacid), surfactants (e.g., isopropyl myristate and sodium laurylsulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes(e.g., menthol), amines, amides, alkanes, alkanols, water, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as polyethylene glycols.

Another exemplary formulation for use in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of a compound of the present invention in controlled amounts,either with or without another agent.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See, e.g., U.S. Pat.Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents.

Pharmaceutical compositions for inhalation. Compositions for inhalationor insufflation include solutions and suspensions in pharmaceuticallyacceptable, aqueous or organic solvents, or mixtures thereof, andpowders. The liquid or solid compositions may contain suitablepharmaceutically acceptable excipients as described supra. Preferablythe compositions are administered by the oral or nasal respiratory routefor local or systemic effect. Compositions in preferablypharmaceutically acceptable solvents may be nebulized by use of inertgases. Nebulized solutions may be inhaled directly from the nebulizingdevice or the nebulizing device may be attached to a face mask tent, orintermittent positive pressure breathing machine. Solution, suspension,or powder compositions may be administered, preferably orally ornasally, from devices that deliver the formulation in an appropriatemanner.

Other pharmaceutical compositions. Pharmaceutical compositions may alsobe prepared from compositions described herein and one or morepharmaceutically acceptable excipients suitable for sublingual, buccal,rectal, intraosseous, intraocular, intranasal, epidural, or intraspinaladministration. Preparations for such pharmaceutical compositions arewell-known in the art. See, e.g., See, e.g., Anderson, Philip O.;Knoben, James E.; Troutman, William G, eds., Handbook of Clinical DrugData, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds.,Principles of Drug Action, Third Edition, Churchill Livingston, N. Y.,1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition,McGraw Hill, 20037ybg; Goodman and Gilman, eds., The PharmacologicalBasis of Therapeutics, Tenth Edition, McGraw Hill, 2001; RemingtonsPharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000;Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (ThePharmaceutical Press, London, 1999); all of which are incorporated byreference herein in their entirety.

Administration of the compounds or pharmaceutical composition of thepresent invention can be effected by any method that enables delivery ofthe compounds to the site of action. These methods include oral routes,intraduodenal routes, parenteral injection (including intravenous,intraarterial, subcutaneous, intramuscular, intravascular,intraperitoneal or infusion), topical (e.g. transdermal application),rectal administration, via local delivery by catheter or stent orthrough inhalation. Compounds can also be administered intraadiposallyor intrathecally.

The amount of the compound administered will be dependent on the mammalbeing treated, the severity of the disorder or condition, the rate ofadministration, the disposition of the compound and the discretion ofthe prescribing physician. However, an effective dosage is in the rangeof about 0.001 to about 100 mg per kg body weight per day, preferablyabout I to about 35 mg/kg/day, in single or divided doses. For a 70 kghuman, this would amount to about 0.05 to 7 g/day, preferably about 0.05to about 2.5 g/day. In some instances, dosage levels below the lowerlimit of the aforesaid range may be more than adequate, while in othercases still larger doses may be employed without causing any harmfulside effect, e.g. by dividing such larger doses into several small dosesfor administration throughout the day.

In some embodiments, a compound of the invention is administered in asingle dose. Typically, such administration will be by injection, e.g.,intravenous injection, in order to introduce the agent quickly. However,other routes may be used as appropriate. A single dose of a compound ofthe invention may also be used for treatment of an acute condition.

In some embodiments, a compound of the invention is administered inmultiple doses. Dosing may be about once, twice, three times, fourtimes, five times, six times, or more than six times per day. Dosing maybe about once a month, once every two weeks, once a week, or once everyother day. In another embodiment a compound of the invention and anotheragent are administered together about once per day to about 6 times perday. In another embodiment the administration of a compound of theinvention and an agent continues for less than about 7 days. In yetanother embodiment the administration continues for more than about 6,10, 14, 28 days, two months, six months, or one year. In some cases,continuous dosing is achieved and maintained as long as necessary.

Administration of the agents of the invention may continue as long asnecessary. In some embodiments, an agent of the invention isadministered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In someembodiments, an agent of the invention is administered for less than 28,14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, an agent of theinvention is administered chronically on an ongoing basis, e.g., for thetreatment of chronic effects.

An effective amount of a compound of the invention may be administeredin either single or multiple doses by any of the accepted modes ofadministration of agents having similar utilities, including rectal,buccal, intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant.

The compositions of the invention may also be delivered via animpregnated or coated device such as a stent, for example, or anartery-inserted cylindrical polymer. Such a method of administrationmay, for example, aid in the prevention or amelioration of restenosisfollowing procedures such as balloon angioplasty. Without being bound bytheory, compounds of the invention may slow or inhibit the migration andproliferation of smooth muscle cells in the arterial wall whichcontribute to restenosis. A compound of the invention may beadministered, for example, by local delivery from the struts of a stent,from a stent graft, from grafts, or from the cover or sheath of a stent.In some embodiments, a compound of the invention is admixed with amatrix. Such a matrix may be a polymeric matrix, and may serve to bondthe compound to the stent. Polymeric matrices suitable for such use,include, for example, lactone-based polyesters or copolyesters such aspolylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides,polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester)copolymers (e.g. PEO-PLLA); polydimethylsiloxane,poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g.polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone),fluorinated polymers such as polytetrafluoroethylene and celluloseesters. Suitable matrices may be nondegrading or may degrade with time,releasing the compound or compounds. Compounds of the invention may beapplied to the surface of the stent by various methods such as dip/spincoating, spray coating, dip-coating, and/or brush-coating. The compoundsmay be applied in a solvent and the solvent may be allowed to evaporate,thus forming a layer of compound onto the stent. Alternatively, thecompound may be located in the body of the stent or graft, for examplein microchannels or micropores. When implanted, the compound diffusesout of the body of the stent to contact the arterial wall. Such stentsmay be prepared by dipping a stent manufactured to contain suchmicropores or microchannels into a solution of the compound of theinvention in a suitable solvent, followed by evaporation of the solvent.Excess drug on the surface of the stent may be removed via an additionalbrief solvent wash. In yet other embodiments, compounds of the inventionmay be covalently linked to a stent or graft. A covalent linker may beused which degrades in vivo, leading to the release of the compound ofthe invention. Any bio-labile linkage may be used for such a purpose,such as ester, amide or anhydride linkages. Compounds of the inventionmay additionally be administered intravascularly from a balloon usedduring angioplasty. Extravascular administration of the compounds viathe pericard or via advential application of formulations of theinvention may also be performed to decrease restenosis.

A variety of stent devices which may be used as described are disclosed,for example, in the following references, all of which are herebyincorporated by reference: U.S. Pat. Nos. 5,451,233; 5,040,548;5,061,273; 5,496,346; 5,292,331; 5,674,278; 3,657,744; 4,739,762;5,195,984; 5,292,331; 5,674,278; 5,879,382; 6,344,053.

The compounds of the invention may be administered in dosages. It isknown in the art that due to intersubject variability in compoundpharmacokinetics, individualization of dosing regimen is necessary foroptimal therapy.

Dosing for a compound of the invention may be found by routineexperimentation in light of the instant disclosure.

When a compound of the invention, is administered in a composition thatcomprises one or more agents, and the agent has a shorter half-life thanthe compound of the invention unit dose forms of the agent and thecompound of the invention may be adjusted accordingly.

The subject pharmaceutical composition may, for example, be in a formsuitable for oral administration as a tablet, capsule, pill, powder,sustained release formulations, solution, suspension, for parenteralinjection as a sterile solution, suspension or emulsion, for topicaladministration as an ointment or cream or for rectal administration as asuppository. The pharmaceutical composition may be in unit dosage formssuitable for single administration of precise dosages. Thepharmaceutical composition will include a conventional pharmaceuticalcarrier or excipient and a compound according to the invention as anactive ingredient. In addition, it may include other medicinal orpharmaceutical agents, carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compound in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

The activity of the compounds of the present invention may be determinedby the following procedure, as well as the procedure described in theexamples below. The activity of the kinase is assessed by measuring theincorporation of γ-³³P-phosphate from γ-³³P-ATP onto N-terminal Histagged substrate, which is expressed in E. coli and is purified byconventional methods, in the presence of the kinase. The assay iscarried out in 96-well polypropylene plate. The incubation mixture (100,μL) comprises of 25 mM Hepes, pH 7.4, 10 mM MgCl₂, 5 mMβ-glycerolphosphate, 100 μM Na-orthovanadate, 5 mM DTT, 5 nM kinase, and1 μM substrate. Inhibitors are suspended in DMSO, and all reactions,including controls are performed at a final concentration of 1% DMSO.Reactions are initiated by the addition of 10 μM ATP (with 0.5 μCiγ-³³P-ATP/well) and incubated at ambient temperature for 45 minutes.Equal volume of 25% TCA is added to stop the reaction and precipitatethe proteins. Precipitated proteins are trapped onto glass fiber Bfilterplates, and excess labeled ATP washed off using a Tomtec MACH IIIharvestor. Plates are allowed to air-dry prior to adding 30 μL/well ofPackard Microscint 20, and plates are counted using a Packard TopCount.

The invention also provides kits. The kits include a compound orcompounds of the present invention as described herein, in suitablepackaging, and written material that can include instructions for use,discussion of clinical studies, listing of side effects, and the like.Such kits may also include information, such as scientific literaturereferences, package insert materials, clinical trial results, and/orsummaries of these and the like, which indicate or establish theactivities and/or advantages of the composition, and/or which describedosing, administration, side effects, drug interactions, or otherinformation useful to the health care provider. Such information may bebased on the results of various studies, for example, studies usingexperimental animals involving in vivo models and studies based on humanclinical trials. The kit may further contain another agent. In someembodiments, the compound of the present invention and the agent areprovided as separate compositions in separate containers within the kit.In some embodiments, the compound of the present invention and the agentare provided as a single composition within a container in the kit.Suitable packaging and additional articles for use (e.g., measuring cupfor liquid preparations, foil wrapping to minimize exposure to air, andthe like) are known in the art and may be included in the kit. Kitsdescribed herein can be provided, marketed and/or promoted to healthproviders, including physicians, nurses, pharmacists, formularyofficials, and the like. Kits may also, in some embodiments, be marketeddirectly to the consumer.

The invention also provides methods of using the compounds orpharmaceutical compositions of the present invention to treat diseaseconditions, including but not limited to diseases associated withmalfunctioning of one or more types of PI3 kinase. A detaileddescription of conditions and disorders mediated by p110δ kinaseactivity is set forth in Sadu et al., WO 01/81346, which is incorporatedherein by reference in its entirety for all purposes.

The treatment methods provided herein comprise administering to thesubject a therapeutically effective amount of a compound of theinvention. In one embodiment, the present invention provides a method oftreating an inflammation disorder, including autoimmune diseases in amammal. The method comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrateor derivative thereof. Examples of autoimmune diseases includes but isnot limited to acute disseminated encephalomyelitis (ADEM), Addison'sdisease, antiphospholipid antibody syndrome (APS), aplastic anemia,autoimmune hepatitis, coeliac disease, Crohn's disease, Diabetesmellitus (type 1), Goodpasture's syndrome, Graves' disease,Guillain-Barré syndrome (GBS), Hashimoto's disease, lupus erythematosus,multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome(OMS), optic neuritis, Ord's thyroiditis, oemphigus, polyarthritis,primary biliary cirrhosis, psoriasis, rheumatoid arthritis, Reiter'ssyndrome, Takayasu's arteritis, temporal arteritis (also known as “giantcell arteritis”), warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, alopecia universalis, Chagas' disease, chronic fatiguesyndrome, dysautonomia, endometriosis, hidradenitis suppurativa,interstitial cystitis, neuromyotonia, sarcoidosis, scleroderma,ulcerative colitis, vitiligo, and vulvodynia. Other disorders includebone-resorption disorders and thromobsis.

In some embodiments, the method of treating inflammatory or autoimmunediseases comprises administering to a subject (e.g. a mammal) atherapeutically effective amount of one or more compounds of the presentinvention that selectively inhibit PI3K-δ and/or PI3K-γ as compared toall other type I PI3 kinases. Such selective inhibition of PI3K-δ and/orPI3K-γ may be advantageous for treating any of the diseases orconditions described herein. For example, selective inhibition of PI3K-δmay inhibit inflammatory responses associated with inflammatorydiseases, autoimmune disease, or diseases related to an undesirableimmune response including but not limited to asthma, emphysema, allergy,dermatitis, rhuematoid arthritis, psoriasis, lupus erythematosus, orgraft versus host disease. Selective inhibition of PI3K-δ may furtherprovide for a reduction in the inflammatory or undesirable immuneresponse without a concomittant reduction in the ability to reduce abacterial, viral, and/or fungal infection. Selective inhibition of bothPI3K-δ and PI3K-γ may be advantageous for inhibiting the inflammatoryresponse in the subject to a greater degree than that would be providedfor by inhibitors that selectively inhibit PI3K-δ or PI3K-γ alone. Inone aspect, one or more of the subject methods are effective in reducingantigen specific antibody production in vivo by about 2-fold, 3-fold,4-fold, 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold,500-fold, 750-fold, or about 1000-fold or more. In another aspect, oneor more of the subject methods are effective in reducing antigenspecific IgG3 and/or IgGM production in vivo by about 2-fold, 3-fold,4-fold, 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold,500-fold, 750-fold, or about 1000-fold or more.

In one aspect, one of more of the subject methods are effective inameliorating symptoms associated with rhuematoid arthritis including butnot limited to a reduction in the swelling of joints, a reduction inserum anti-collagen levels, and/or a reduction in joint pathology suchas bone resorption, cartilage damage, pannus, and/or inflammation. Inanother aspect, the subject methods are effective in reducing ankleinflammation by at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%,60%, or about 75% to 90%. In another aspect, the subject methods areeffective in reducing knee inflammation by at least about 2%, 5%, 10%,15%, 20%, 25%, 30%, 50%, 60%, or about 75% to 90% or more. In stillanother aspect, the subject methods are effective in reducing serumanti-type II collagen levels by at least about 10%, 12%, 15%, 20%, 24%,25%, 30%, 35%, 50%, 60%, 75%, 80%, 86%, 87%, or about 90% or more. Inanother aspect, the subject methods are effective in reducing anklehistopathology scores by about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%,60%, 75%, 80%, 90% or more. In still another aspect, the subject methodsare effective in reducing knee histopathology scores by about 5%, 10%,15%, 20%, 25%, 30%, 40%, 50%, 60%, 75%, 80%, 90% or more.

In other embodiments, the present invention provides methods of usingthe compounds or pharmaceutical compositions to treat respiratorydiseases including but not limited to diseases affecting the lobes oflung, pleural cavity, bronchial tubes, trachea, upper respiratory tract,or the nerves and muscle for breathing. For example, methods areprovided to treat obstructive pulmonary disease. Chronic obstructivepulmonary disease (COPD) is an umbrella term for a group of respiratorytract diseases that are characterized by airflow obstruction orlimitation. Conditions included in this umbrella term are: chronicbronchitis, emphysema, and bronchiectasis.

In another embodiment, the compounds described herein are used for thetreatment of asthma. Also, the compounds or pharmaceutical compositionsdescribed herein may be used for the treatment of endotoxemia andsepsis. In one embodiment, the compounds or pharmaceutical compositionsdescribed herein are used to for the treatment of rheumatoid arthritis(RA). In yet another embodiment, the compounds or pharmaceuticalcompositions described herein is used for the treatment of contact oratopic dermatitis. Contact dermatitis includes irritant dermatitis,phototoxic dermatitis, allergic dermatitis, photoallergic dermatitis,contact urticaria, systemic contact-type dermatitis and the like.Irritant dermatitis can occur when too much of a substance is used onthe skin of when the skin is sensitive to certain substance. Atopicdermatitis, sometimes called eczema, is a kind of dermatitis, an atopicskin disease.

The invention also relates to a method of treating a hyperproliferativedisorder in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrateor derivative thereof. In some embodiments, said method relates to thetreatment of cancer such as acute myeloid leukemia, thymus, brain, lung,squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oralcavity and oropharyngeal, bladder, gastric, stomach, pancreatic,bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian,prostate, colorectal, esophageal, testicular, gynecological, thyroid,CNS, PNS, AIDS-related (e.g. Lymphoma and Kaposi's Sarcoma) orviral-induced cancer. In some embodiments, said method relates to thetreatment of a non-cancerous hyperproliferative disorder such as benignhyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).

The invention also relates to a method of treating diseases related tovasculogenesis or angiogenesis in a mammal that comprises administeringto said mammal a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, ester,prodrug, solvate, hydrate or derivative thereof. In some embodiments,said method is for treating a disease selected from the group consistingof tumor angiogenesis, chronic inflammatory disease such as rheumatoidarthritis, atherosclerosis, inflammatory bowel disease, skin diseasessuch as psoriasis, eczema, and scleroderma, diabetes, diabeticretinopathy, retinopathy of prematurity, age-related maculardegeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

Patients that can be treated with compounds of the present invention, orpharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative of said compounds, according to the methods of this inventioninclude, for example, patients that have been diagnosed as havingpsoriasis; restenosis; atherosclerosis; BPH; breast cancer such as aductal carcinoma in duct tissue in a mammary gland, medullarycarcinomas, colloid carcinomas, tubular carcinomas, and inflammatorybreast cancer; ovarian cancer, including epithelial ovarian tumors suchas adenocarcinoma in the ovary and an adenocarcinoma that has migratedfrom the ovary into the abdominal cavity; uterine cancer; cervicalcancer such as adenocarcinoma in the cervix epithelial includingsquamous cell carcinoma and adenocarcinomas; prostate cancer, such as aprostate cancer selected from the following: an adenocarcinoma or anadenocarinoma that has migrated to the bone; pancreatic cancer such asepitheliod carcinoma in the pancreatic duct tissue and an adenocarcinomain a pancreatic duct; bladder cancer such as a transitional cellcarcinoma in urinary bladder, urothelial carcinomas (transitional cellcarcinomas), tumors in the urothelial cells that line the bladder,squamous cell carcinomas, adenocarcinomas, and small cell cancers;leukemia such as acute myeloid leukemia (AML), acute lymphocyticleukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairycell leukemia, myelodysplasia, myeloproliferative disorders, acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML),mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM),and myelodysplastic syndrome (MDS); bone cancer; lung cancer such asnon-small cell lung cancer (NSCLC), which is divided into squamous cellcarcinomas, adenocarcinomas, and large cell undifferentiated carcinomas,and small cell lung cancer; skin cancer such as basal cell carcinoma,melanoma, squamous cell carcinoma and actinic keratosis, which is a skincondition that sometimes develops into squamous cell carcinoma; eyeretinoblastoma; cutaneous or intraocular (eye) melanoma; primary livercancer (cancer that begins in the liver); kidney cancer; thyroid cancersuch as papillary, follicular, medullary and anaplastic; AIDS-relatedlymphoma such as diffuse large B-cell lymphoma, B-cell immunoblasticlymphoma and small non-cleaved cell lymphoma; Kaposi's Sarcoma;viral-induced cancers including hepatitis B virus (HBV), hepatitis Cvirus (HCV), and hepatocellular carcinoma; human lymphotropic virus-type1 (HTLV-1) and adult T-cell leukemia/lymphoma; and human papilloma virus(HPV) and cervical cancer; central nervous system cancers (CNS) such asprimary brain tumor, which includes gliomas (astrocytoma, anaplasticastrocytoma, or glioblastoma multiforme), Oligodendroglioma, Ependymoma,Meningioma, Lymphoma, Schwannoma, and Medulloblastoma; peripheralnervous system (PNS) cancers such as acoustic neuromas and malignantperipheral nerve sheath tumor (MPNST) including neurofibromas andschwannomas, malignant fibrous cytoma, malignant fibrous histiocytoma,malignant meningioma, malignant mesothelioma, and malignant mixedMüllerian tumor; oral cavity and oropharyngeal cancer such as,hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, andoropharyngeal cancer; stomach cancer such as lymphomas, gastric stromaltumors, and carcinoid tumors; testicular cancer such as germ cell tumors(GCTs), which include seminomas and nonseminomas, and gonadal stromaltumors, which include Leydig cell tumors and Sertoli cell tumors; thymuscancer such as to thymomas, thymic carcinomas, Hodgkin disease,non-Hodgkin lymphomas carcinoids or carcinoid tumors; rectal cancer; andcolon cancer.

The invention also relates to a method of treating diabetes in a mammalthat comprises administering to said mammal a therapeutically effectiveamount of a compound of the present invention, or a pharmaceuticallyacceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

In addition, the compounds described herein may be used to treat acne.

In addition, the compounds described herein may be used for thetreatment of arteriosclerosis, including atherosclerosis.Arteriosclerosis is a general term describing any hardening of medium orlarge arteries. Atherosclerosis is a hardening of an artery specificallydue to an atheromatous plaque.

Further the compounds described herein may be used for the treatment ofglomerulonephritis. Glomerulonephritis is a primary or secondaryautoimmune renal disease characterized by inflammation of the glomeruli.It may be asymptomatic, or present with hematuria and/or proteinuria.There are many recognized types, divided in acute, subacute or chronicglomerulonephritis. Causes are infectious (bacterial, viral or parasiticpathogens), autoimmune or paraneoplastic.

Additionally, the compounds described herein may be used for thetreatment of bursitis, lupus, acute disseminated encephalomyelitis(ADEM), addison's disease, antiphospholipid antibody syndrome (APS),aplastic anemia, autoimmune hepatitis, coeliac disease, crohn's disease,diabetes mellitus (type 1), goodpasture's syndrome, graves' disease,guillain-barr6 syndrome (GBS), hashimoto's disease, inflammatory boweldisease, lupus erythematosus, myasthenia gravis, opsoclonus myoclonussyndrome (OMS), optic neuritis, ord's thyroiditis, ostheoarthritis,uveoretinitis, pemphigus, polyarthritis, primary biliary cirrhosis,reiter's syndrome, takayasu's arteritis, temporal arteritis, warmautoimmune hemolytic anemia, wegener's granulomatosis, alopeciauniversalis, chagas' disease, chronic fatigue syndrome, dysautonomia,endometriosis, hidradenitis suppurativa, interstitial cystitis,neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo,vulvodynia, appendicitis, arteritis, arthritis, blepharitis,bronchiolitis, bronchitis, cervicitis, cholangitis, cholecystitis,chorioamnionitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, gingivitis, hepatitis, hidradenitis, ileitis, iritis,laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis,nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

The invention also relates to a method of treating a cardiovasculardisease in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrateor derivative thereof. Examples of cardiovascular conditions include,but are not limited to, atherosclerosis, restenosis, vascular occlusionand carotid obstructive disease.

In another aspect, the present invention provides methods of disruptingthe function of a leukocyte or disrupting a function of an osteoclast.The method includes contacting the leukocyte or the osteoclast with afunction disrupting amount of a compound of the invention.

In another aspect of the present invention, methods are provided fortreating ophthalmic disease by administering one or more of the subjectcompounds or pharmaceutical compositions to the eye of a subject.

Methods are further provided for administering the compounds of thepresent invention via eye drop, intraocular injection, intravitrealinjection, topically, or through the use of a drug eluting device,microcapsule, implant, or microfluidic device. In some cases, thecompounds of the present invention are administered with a carrier orexcipient that increases the intraocular penetrance of the compound suchas an oil and water emulsion with colloid particles having an oily coresurrounded by an interfacial film.

In some cases, the colloid particles include at least one cationic agentand at least one non-ionic sufactant such as a poloxamer, tyloxapol, apolysorbate, a polyoxyethylene castor oil derivative, a sorbitan ester,or a polyoxyl stearate. In some cases, the cationic agent is analkylamine, a tertiary alkyl amine, a quarternary ammonium compound, acationic lipid, an amino alcohol, a biguanidine salt, a cationiccompound or a mixture thereof. In some cases the cationic agent is abiguanidine salt such as chlorhexidine, polyaminopropyl biguanidine,phenformin, alkylbiguanidine, or a mixture thereof. In some cases, thequaternary ammonium compound is a benzalkonium halide, lauralkoniumhalide, cetrimide, hexadecyltrimethylammonium halide,tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide,cetrimonium halide, benzethonium halide, behenalkonium halide,cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide,benzododecinium halide, chlorallyl methenamine halide, myristylalkoniumhalide, stearalkonium halide or a mixture of two or more thereof. Insome cases, cationic agent is a benzalkonium chloride, lauralkoniumchloride, benzododecinium bromide, benzethenium chloride,hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,dodecyltrimethylammonium bromide or a mixture of two or more thereof. Insome cases, the oil phase is mineral oil and light mineral oil, mediumchain triglycerides (MCT), coconut oil; hydrogenated oils comprisinghydrogenated cottonseed oil, hydrogenated palm oil, hydrogenate castoroil or hydrogenated soybean oil; polyoxyethylene hydrogenated castor oilderivatives comprising poluoxyl-40 hydrogenated castor oil, polyoxyl-60hydrogenated castor oil or polyoxyl-100 hydrogenated castor oil.

The invention further provides methods of modulating kinase activity bycontacting a kinase with an amount of a compound of the inventionsufficient to modulate the activity of the kinase. Modulate can beinhibiting or activating kinase activity. In some embodiments, theinvention provides methods of inhibiting kinase activity by contacting akinase with an amount of a compound of the invention sufficient toinhibit the activity of the kinase. In some embodiments, the inventionprovides methods of inhibiting kinase activity in a solution bycontacting said solution with an amount of a compound of the inventionsufficient to inhibit the activity of the kinase in said solution. Insome embodiments, the invention provides methods of inhibiting kinaseactivity in a cell by contacting said cell with an amount of a compoundof the invention sufficient to inhibit the activity of the kinase insaid cell. In some embodiments, the invention provides methods ofinhibiting kinase activity in a tissue by contacting said tissue with anamount of a compound of the invention sufficient to inhibit the activityof the kinase in said tissue. In some embodiments, the inventionprovides methods of inhibiting kinase activity in an organism bycontacting said organism with an amount of a compound of the inventionsufficient to inhibit the activity of the kinase in said organism. Insome embodiments, the invention provides methods of inhibiting kinaseactivity in an animal by contacting said animal with an amount of acompound of the invention sufficient to inhibit the activity of thekinase in said animal. In some embodiments, the invention providesmethods of inhibiting kinase activity in a mammal by contacting saidmammal with an amount of a compound of the invention sufficient toinhibit the activity of the kinase in said mammal. In some embodiments,the invention provides methods of inhibiting kinase activity in a humanby contacting said human with an amount of a compound of the inventionsufficient to inhibit the activity of the kinase in said human. In someembodiments, the % of kinase activity after contacting a kinase with acompound of the invention is less than 1, 5, 10, 20, 30, 40, 50, 60, 70,80 90, 95, or 99% of the kinase activity in the absence of saidcontacting step.

In some embodiments, the kinase is a lipid kinase or a protein kinase.In some embodiments, the kinase is selected from the group consisting ofPI3 kinase including different isorforms such as PI3 kinase α, PI3kinase β, PI3 kinase γ, PI3 kinase δ; DNA-PK; mTor; Abl, VEGFR, Ephrinreceptor B4 (EphB4); TEK receptor tyrosine kinase (TIE2); FMS-relatedtyrosine kinase 3 (FLT-3); Platelet derived growth factor receptor(PDGFR); RET; ATM; ATR; hSmg-1; Hck; Src; Epidermal growth factorreceptor (EGFR); KIT; Inulsin Receptor (IR) and IGFR.

The invention further provides methods of modulating PI3 kinase activityby contacting a PI3 kinase with an amount of a compound of the inventionsufficient to modulate the activity of the PI3 kinase. Modulate can beinhibiting or activating PI3 kinase activity. In some embodiments, theinvention provides methods of inhibiting PI3 kinase activity bycontacting a PI3 kinase with an amount of a compound of the inventionsufficient to inhibit the activity of the PI3 kinase. In someembodiments, the invention provides methods of inhibiting PI3 kinaseactivity. Such inhibition can take place in solution, in a cellexpressing one or more PI3 kinases, in a tissue comprising a cellexpressing one or more PI3 kinases, or in an organism expressing one ormore PI3 kinases. In some embodiments, the invention provides methods ofinhibiting PI3 kinase activity in an animal (including mammal such ashumans) by contacting said animal with an amount of a compound of theinvention sufficient to inhibit the activity of the PI3 kinase in saidanimal.

The present invention also provides methods for combination therapies inwhich an agent known to modulate other pathways, or other components ofthe same pathway, or even overlapping sets of target enzymes are used incombination with a compound of the present invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof. In one aspect, such therapy includes but is notlimited to the combination of the subject compound with chemotherapeuticagents, therapeutic antibodies, and radiation treatment, to provide asynergistic or additive therapeutic effect.

In one aspect, the compounds or pharmaceutical compositions of thepresent invention may present synergistic or additive efficacy whenadministered in combination with agents that inhibit IgE production oractivity. Such combination can reduce the undesired effect of high levelof IgE associated with the use of one or more PI3Kδ inhibitors, if sucheffect occurs. This may be particularly useful in treatment ofautoimmune and inflammatory disorders (AIID) such as rheumatoidarthritis. Additionally, the administration of PI3Kδ or PI3Kδ/γinhibitors of the present invention in combination with inhibitors ofmTOR may also exhibit synergy through enhanced inhibition of the PI3Kpathway.

In a separate but related aspect, the present invention provides acombination treatment of a disease associated with PI3Kδ comprisingadministering to a PI3Kδ inhibitor and an agent that inhibits IgEproduction or activity. Other exemplary PI3Kδ inhibitors are applicableand they are described, e.g., U.S. Pat. No. 6,800,620. Such combinationtreatment is particularly useful for treating autoimmune andinflammatory diseases (AIID) including but not limited to rheumatoidarthritis.

Agents that inhibit IgE production are known in the art and they includebut are not limited to one or more of TEI-9874,2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,rapamycin, rapamycin analogs (i.e. rapalogs), TORC1 inhibitors, TORC2inhibitors, and any other compounds that inhibit mTORC1 and mTORC2.Agents that inhibit IgE activity include, for example, anti-IgEantibodies such as for example Omalizumab and TNX-901.

For treatment of autoimmune diseases, the subject compounds orpharmaceutical compositions can be used in combination with commonlyprescribed drugs including but not limited to Enbrel®, Remicade®,Humira®, Avonex®, and Rebif®. For treatment of respiratory diseases, thesubject compounds or pharmaceutical compositions can be administered incombination with commonly prescribed drugs including but not limited toXolair®, Advair®, Singulair®, and Spiriva®.

The compounds of the invention may be formulated or administered inconjunction with other agents that act to relieve the symptoms ofinflammatory conditions such as encephalomyelitis, asthma, and the otherdiseases described herein. These agents include non-steroidalanti-inflammatory drugs (NSAIDs), e.g. acetylsalicylic acid; ibuprofen;naproxen; indomethacin; nabumetone; tolmetin; etc. Corticosteroids areused to reduce inflammation and suppress activity of the immune system.The most commonly prescribed drug of this type is Prednisone.Chloroquine (Aralen) or hydroxychloroquine (Plaquenil) may also be veryuseful in some individuals with lupus. They are most often prescribedfor skin and joint symptoms of lupus. Azathioprine (Imuran) andcyclophosphamide (Cytoxan) suppress inflammation and tend to suppressthe immune system. Other agents, e.g. methotrexate and cyclosporin areused to control the symptoms of lupus. Anticoagulants are employed toprevent blood from clotting rapidly. They range from aspirin at very lowdose which prevents platelets from sticking, to heparin/coumadin.

In another one aspect, this invention also relates to a pharmaceuticalcomposition for inhibiting abnormal cell growth in a mammal whichcomprises an amount of a compound of the present invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof, in combination with an amount of an anti-canceragent (e.g. a chemotherapeutic agent). Many chemotherapeutics arepresently known in the art and can be used in combination with thecompounds of the invention.

In some embodiments, the chemotherapeutic is selected from the groupconsisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.Non-limiting examples are chemotherapeutic agents, cytotoxic agents, andnon-peptide small molecules such as Gleevec (Imatinib Mesylate), Velcade(bortezomib), Casodex (bicalutamide), Iressa (gefitinib), and Adriamycinas well as a host of chemotherapeutic agents. Non-limiting examples ofchemotherapeutic agents include alkylating agents such as thiotepa andcyclosphosphamide (CYTOXAN™); alkyl sulfonates such as busulfan,improsulfan and piposulfan; aziridines such as benzodopa, carboquone,meturedopa, and uredopa; ethylenimines and methylamelamines includingaltretamine, triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; nitrogenmustards such as chlorambucil, chlornaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine,bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin,carzinophilin, Casodex™, chromomycins, dactinomycin, daunorubicin,detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin,esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid,nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone;mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazide; procarbazine; PSK.R™; razoxane; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethyla-mine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, N.J.) anddocetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoicacid; esperamicins; capecitabine; and pharmaceutically acceptable salts,acids or derivatives of any of the above. Also included as suitablechemotherapeutic cell conditioners are anti-hormonal agents that act toregulate or inhibit hormone action on tumors such as anti-estrogensincluding for example tamoxifen (Nolvadex™), raloxifene, aromataseinhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene,LY 117018, onapristone, and toremifene (Fareston); and anti-androgenssuch as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin;chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate;platinum analogs such as cisplatin and carboplatin; vinblastine;platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone;vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin;aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11);topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO). Wheredesired, the compounds or pharmaceutical composition of the presentinvention can be used in combination with commonly prescribedanti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®,Taxol®, Arimidex®, Taxotere®, and Velcade®.

This invention further relates to a method for using the compounds orpharmaceutical composition in combination with radiation therapy ininhibiting abnormal cell growth or treating the hyperproliferativedisorder in the mammal. Techniques for administering radiation therapyare known in the art, and these techniques can be used in thecombination therapy described herein. The administration of the compoundof the invention in this combination therapy can be determined asdescribed herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g. At-211,I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner of the present invention include both solids andliquids. By way of non-limiting example, the radiation source can be aradionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source,I-125 as a solid source, or other radionuclides that emit photons, betaparticles, gamma radiation, or other therapeutic rays. The radioactivematerial can also be a fluid made from any solution of radionuclide(s),e.g., a solution of I-125 or I-131, or a radioactive fluid can beproduced using a slurry of a suitable fluid containing small particlesof solid radionuclides, such as Au-198, Y-90. Moreover, theradionuclide(s) can be embodied in a gel or radioactive micro spheres.

Without being limited by any theory, the compounds of the presentinvention can render abnormal cells more sensitive to treatment withradiation for purposes of killing and/or inhibiting the growth of suchcells. Accordingly, this invention further relates to a method forsensitizing abnormal cells in a mammal to treatment with radiation whichcomprises administering to the mammal an amount of a compound of thepresent invention or pharmaceutically acceptable salt, ester, prodrug,solvate, hydrate or derivative thereof, which amount is effective issensitizing abnormal cells to treatment with radiation. The amount ofthe compound, salt, or solvate in this method can be determinedaccording to the means for ascertaining effective amounts of suchcompounds described herein.

The compounds or pharmaceutical compositions of the present inventioncan be used in combination with an amount of one or more substancesselected from anti-angiogenesis agents, signal transduction inhibitors,and antiproliferative agents.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-11(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound of the present invention and pharmaceutical compositionsdescribed herein. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172 (publishedOct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European PatentApplication No. 97304971.1 (filed Jul. 8, 1997), European PatentApplication No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (publishedFeb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16,1998), European Patent Publication 606,046 (published Jul. 13, 1994),European Patent Publication 931, 788 (published Jul. 28, 1999), WO90/05719 (published May 31, 1990), WO 99/52910 (published Oct. 21,1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (publishedJun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filedJul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar.25, 1999), Great Britain Patent Application No. 9912961.1 (filed Jun. 3,1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12,1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No.5,861,510 (issued Jan. 19, 1999), and European Patent Publication780,386 (published Jun. 25, 1997), all of which are incorporated hereinin their entireties by reference. Preferred MMP-2 and MMP-9 inhibitorsare those that have little or no activity inhibiting MMP-1. Morepreferred, are those that selectively inhibit MMP-2 and/or AMP-9relative to the other matrix-metalloproteinases (i. e., MAP-1, MMP-3,MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).Some specific examples of MMP inhibitors useful in the present inventionare AG-3340, RO 32-3555, and RS 13-0830.

The invention also relates to a method of and to a pharmaceuticalcomposition of treating a cardiovascular disease in a mammal whichcomprises an amount of a compound of the present invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, hydrate orderivative thereof, or an isotopically-labeled derivative thereof, andan amount of one or more therapeutic agents use for the treatment ofcardiovascular diseases.

Examples for use in cardiovascular disease applications areanti-thrombotic agents, e.g., prostacyclin and salicylates, thrombolyticagents, e.g., streptokinase, urokinase, tissue plasminogen activator(TPA) and anisoylated plasminogen-streptokinase activator complex(APSAC), anti-platelets agents, e.g., acetyl-salicylic acid (ASA) andclopidrogel, vasodilating agents, e.g., nitrates, calcium channelblocking drugs, anti-proliferative agents, e.g., colchicine andalkylating agents, intercalating agents, growth modulating factors suchas interleukins, transformation growth factor-beta and congeners ofplatelet derived growth factor, monoclonal antibodies directed againstgrowth factors, anti-inflammatory agents, both steroidal andnon-steroidal, and other agents that can modulate vessel tone, function,arteriosclerosis, and the healing response to vessel or organ injurypost intervention. Antibiotics can also be included in combinations orcoatings comprised by the invention. Moreover, a coating can be used toeffect therapeutic delivery focally within the vessel wall. Byincorporation of the active agent in a swellable polymer, the activeagent will be released upon swelling of the polymer.

The compounds describe herein may be formulated or administered inconjunction with liquid or solid tissue barriers also known aslubricants. Examples of tissue barriers include, but are not limited to,polysaccharides, polyglycans, seprafilm, interceed and hyaluronic acid.

Medicaments which may be administered in conjunction with the compoundsdescribed herein include any suitable drugs usefully delivered byinhalation for example, analgesics, e.g. codeine, dihydromorphine,ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem;antiallergics, e.g. cromoglycate, ketotifen or nedocromil;anti-infectives, e.g. cephalosporins, penicillins, streptomycin,sulphonamides, tetracyclines or pentamidine; antihistamines, e.g.methapyrilene; anti-inflammatories, e.g. beclomethasone, flunisolide,budesonide, tipredane, triamcinolone acetonide or fluticasone;antitussives, e.g. noscapine; bronchodilators, e.g. ephedrine,adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol,phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol,salbutamol, salmeterol, terbutalin, isoetharine, tulobuterol,orciprenaline or(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol;diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, atropineor oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone;xanthines e.g. aminophylline, choline theophyllinate, lysinetheophyllinate or theophylline; and therapeutic proteins and peptides,e.g. insulin or glucagon. It will be clear to a person skilled in theart that, where appropriate, the medicaments may be used in the form ofsalts (e.g. as alkali metal or amine salts or as acid addition salts) oras esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) tooptimize the activity and/or stability of the medicament.

Other exemplary therapeutic agents useful for a combination therapyinclude but are not limited to agents as described above, radiationtherapy, hormone antagonists, hormones and their releasing factors,thyroid and antithyroid drugs, estrogens and progestins, androgens,adrenocorticotropic hormone; adrenocortical steroids and their syntheticanalogs; inhibitors of the synthesis and actions of adrenocorticalhormones, insulin, oral hypoglycemic agents, and the pharmacology of theendocrine pancreas, agents affecting calcification and bone turnover:calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitaminssuch as water-soluble vitamins, vitamin B complex, ascorbic acid,fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines,chemokines, muscarinic receptor agonists and antagonists;anticholinesterase agents; agents acting at the neuromuscular junctionand/or autonomic ganglia; catecholamines, sympathomimetic drugs, andadrenergic receptor agonists or antagonists; and 5-hydroxytryptamine(5-HT, serotonin) receptor agonists and antagonists.

Therapeutic agents can also include agents for pain and inflammationsuch as histamine and histamine antagonists, bradykinin and bradykininantagonists, 5-hydroxytryptamine (serotonin), lipid substances that aregenerated by biotransformation of the products of the selectivehydrolysis of membrane phospholipids, eicosanoids, prostaglandins,thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatoryagents, analgesic-antipyretic agents, agents that inhibit the synthesisof prostaglandins and thromboxanes, selective inhibitors of theinducible cyclooxygenase, selective inhibitors of the induciblecyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin,cytokines that mediate interactions involved in humoral and cellularimmune responses, lipid-derived autacoids, eicosanoids, P-adrenergicagonists, ipratropium, glucocorticoids, methylxanthines, sodium channelblockers, opioid receptor agonists, calcium channel blockers, membranestabilizers and leukotriene inhibitors.

Additional therapeutic agents contemplated herein include diuretics,vasopressin, agents affecting the renal conservation of water, rennin,angiotensin, agents useful in the treatment of myocardial ischemia,anti-hypertensive agents, angiotensin converting enzyme inhibitors,P3-adrenergic receptor antagonists, agents for the treatment ofhypercholesterolemia, and agents for the treatment of dyslipidemia.

Other therapeutic agents contemplated include drugs used for control ofgastric acidity, agents for the treatment of peptic ulcers, agents forthe treatment of gastroesophageal reflux disease, prokinetic agents,antiemetics, agents used in irritable bowel syndrome, agents used fordiarrhea, agents used for constipation, agents used for inflammatorybowel disease, agents used for biliary disease, agents used forpancreatic disease. Therapeutic agents used to treat protozoaninfections, drugs used to treat Malaria, Amebiasis, Giardiasis,Trichomoniasis, Trypanosomiasis, and/or Leishmaniasis, and/or drugs usedin the chemotherapy of helminthiasis. Other therapeutic agents includeantimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazolequinolones, and agents for urinary tract infections, penicillins,cephalosporins, and other, 3-Lactam antibiotics, an agent comprising anaminoglycoside, protein synthesis inhibitors, drugs used in thechemotherapy of tuberculosis, mycobacterium avium complex disease, andleprosy, antifungal agents, antiviral agents including nonretroviralagents and antiretroviral agents.

Examples of therapeutic antibodies that can be combined with a subjectcompound include but are not limited to anti-receptor tyrosine kinaseantibodies (cetuximab, panitumumab, trastuzumab), anti CD20 antibodies(rituximab, tositumomab), and other antibodies such as alemtuzumab,bevacizumab, and gemtuzumab.

Moreover, therapeutic agents used for immunomodulation, such asimmunomodulators, immunosuppressive agents, tolerogens, andimmunostimulants are contemplated by the methods herein. In addition,therapeutic agents acting on the blood and the blood-forming organs,hematopoietic agents, growth factors, minerals, and vitamins,anticoagulant, thrombolytic, and antiplatelet drugs.

Further therapeutic agents that can be combined with a subject compoundmay be found in Goodman and Gilman's “The Pharmacological Basis ofTherapeutics” Tenth Edition edited by Hardman, Limbird and Gilman or thePhysician's Desk Reference, both of which are incorporated herein byreference in their entirety.

The compounds described herein can be used in combination with theagents disclosed herein or other suitable agents, depending on thecondition being treated. Hence, in some embodiments the compounds of theinvention will be co-administer with other agents as described above.When used in combination therapy, the compounds described herein may beadministered with the second agent simultaneously or separately. Thisadministration in combination can include simultaneous administration ofthe two agents in the same dosage form, simultaneous administration inseparate dosage forms, and separate administration. That is, a compounddescribed herein and any of the agents described above can be formulatedtogether in the same dosage form and administered simultaneously.Alternatively, a compound of the present invention and any of the agentsdescribed above can be simultaneously administered, wherein both theagents are present in separate formulations. In another alternative, acompound of the present invention can be administered just followed byand any of the agents described above, or vice versa. In the separateadministration protocol, a compound of the present invention and any ofthe agents described above may be administered a few minutes apart, or afew hours apart, or a few days apart.

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

Administration of the compounds of the present invention can be effectedby any method that enables delivery of the compounds to the site ofaction. These methods include oral routes, intraduodenal routes,parenteral injection (including intravenous, intraarterial,subcutaneous, intramuscular, intravascular, intraperitoneal orinfusion), topical (e.g. transdermal application), rectaladministration, via local delivery by catheter or stent. Compounds canalso abe administered intraadiposally or intrathecally.

The amount of the compound administered will be dependent on the mammalbeing treated, the severity of the disorder or condition, the rate ofadministration, the disposition of the compound and the discretion ofthe prescribing physician. However, an effective dosage is in the rangeof about 0.001 to about 100 mg per kg body weight per day, preferablyabout 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kghuman, this would amount to about 0.05 to 7 g/day, preferably about 0.05to about 2.5 g/day. In some instances, dosage levels below the lowerlimit of the aforesaid range may be more than adequate, while in othercases still larger doses may be employed without causing any harmfulside effect, e.g. by dividing such larger doses into several small dosesfor administration throughout the day.

The compound may be applied as a sole therapy or may involve one or moreother anti-tumor substances, for example those selected from, mitoticinhibitors, for example vinblastine; alkylating agents, for examplecis-platin, carboplatin and cyclophosphamide; anti-metabolites, forexample 5-fluorouracil, cytosine arabinside and hydroxyurea, or, forexample, one of the preferred anti-metabolites disclosed in EuropeanPatent Application No. 239362 such as N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-yhnethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; growth factor inhibitors; cell cycle inhibitors; intercalatingantibiotics, for example adriamycin and bleomycin; enzymes, for example,interferon; and anti-hormones, for example anti-estrogens such asNolvadex™ (tamoxifen) or, for example anti-androgens such as Casodex™(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide). Such conjoint treatment may be achieved by way of thesimultaneous, sequential or separate dosing of the individual componentsof treatment.

In some embodiments, a compound of the invention is administered in asingle dose. Typically, such administration will be by injection, e.g.,intravenous injection, in order to introduce the agent quickly. However,other routes may be used as appropriate. A single dose of a compound ofthe invention may also be used for treatment of an acute condition.

In some embodiments, a compound of the invention is administered inmultiple doses. Dosing may be about once, twice, three times, fourtimes, five times, six times, or more than six times per day. Dosing maybe about once a month, once every two weeks, once a week, or once everyother day. In another embodiment a compound of the invention and anotheragent are administered together about once per day to about 6 times perday. In another embodiment the administration of a compound of theinvention and an agent continues for less than about 7 days. In yetanother embodiment the administration continues for more than about 6,10, 14, 28 days, two months, six months, or one year. In some cases,continuous dosing is achieved and maintained as long as necessary.

Administration of the agents of the invention may continue as long asnecessary. In some embodiments, an agent of the invention isadministered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In someembodiments, an agent of the invention is administered for less than 28,14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, an agent of theinvention is administered chronically on an ongoing basis, e.g., for thetreatment of chronic effects.

An effective amount of a compound of the invention may be administeredin either single or multiple doses by any of the accepted modes ofadministration of agents having similar utilities, including rectal,buccal, intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant.

The compositions of the invention may also be delivered via animpregnated or coated device such as a stent, for example, or anartery-inserted cylindrical polymer. Such a method of administrationmay, for example, aid in the prevention or amelioration of restenosisfollowing procedures such as balloon angioplasty. Without being bound bytheory, compounds of the invention may slow or inhibit the migration andproliferation of smooth muscle cells in the arterial wall whichcontribute to restenosis. A compound of the invention may beadministered, for example, by local delivery from the struts of a stent,from a stent graft, from grafts, or from the cover or sheath of a stent.In some embodiments, a compound of the invention is admixed with amatrix. Such a matrix may be a polymeric matrix, and may serve to bondthe compound to the stent. Polymeric matrices suitable for such use,include, for example, lactone-based polyesters or copolyesters such aspolylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides,polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester)copolymers (e.g. PEO-PLLA); polydimethylsiloxane,poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g.polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone),fluorinated polymers such as polytetrafluoroethylene and celluloseesters. Suitable matrices may be nondegrading or may degrade with time,releasing the compound or compounds. Compounds of the invention may beapplied to the surface of the stent by various methods such as dip/spincoating, spray coating, dip-coating, and/or brush-coating. The compoundsmay be applied in a solvent and the solvent may be allowed to evaporate,thus forming a layer of compound onto the stent. Alternatively, thecompound may be located in the body of the stent or graft, for examplein microchannels or micropores. When implanted, the compound diffusesout of the body of the stent to contact the arterial wall. Such stentsmay be prepared by dipping a stent manufactured to contain suchmicropores or microchannels into a solution of the compound of theinvention in a suitable solvent, followed by evaporation of the solvent.Excess drug on the surface of the stent may be removed via an additionalbrief solvent wash. In yet other embodiments, compounds of the inventionmay be covalently linked to a stent or graft. A covalent linker may beused which degrades in vivo, leading to the release of the compound ofthe invention. Any bio-labile linkage may be used for such a purpose,such as ester, amide or anhydride linkages. Compounds of the inventionmay additionally be administered intravascularly from a balloon usedduring angioplasty. Extravascular administration of the compounds viathe pericard or via advential application of formulations of theinvention may also be performed to decrease restenosis.

A variety of stent devices which may be used as described are disclosed,for example, in the following references, all of which are herebyincorporated by reference: U.S. Pat. Nos. 5,451,233; 5,040,548;5,061,273; 5,496,346; 5,292,331; 5,674,278; 3,657,744; 4,739,762;5,195,984; 5,292,331; 5,674,278; 5,879,382; 6,344,053; 4,762,129;6,152,946; 6,663,652; 6,027,520; 6,676,682; 6,663,652; 6,872,216;6,027,520; 6,114,653; 5,852,277; 5,843,120; 5,643,312; 5,733,303;5,597,378; 5,653,727; 4,762,129; 5,922,021; 3,657,744; 4,739,762;5,195,984; 5,451,233; 3,657,744; 4,739,762; 5,195,984; 4,739,762;3,657,744; 4,739,762; 5,195,984; 5,292,331; 5,674,278; 5,643,312;5,879,370; 5,421,955; 5,514,154; 5,603,721; 5,421,955; 5,514,154;5,603,721; 5,292,331; 5,674,278; 5,879,382; 6,344,053; 5,728,067;5,980,486; 6,129,708; 5,733,303; 5,843,120; 5,972,018; 5,972,018;5,733,303; 5,843,120; 4,739,762; 5,195,984; 5,902,332; 5,156,594;5,395,334; 6,090,083; 5,639,278; 6,051,020; 6,117,167; 5,632,772;6,165,213; 4,762,129; 5,156,594; 5,217,482; 5,395,334; 4,641,653;4,739,762; 5,922,021; 5,895,406; 6,251,920; 6,120,536; 5,292,331;5,674,278; 5,879,382; 6,344,053; 5,609,627; 6,251,920; 5,733,303;5,843,120; 5,972,018; 6,344,053; 5,292,331; 5,674,278; 5,879,382;5,653,760; 6,190,358; 6,210,364; 6,283,939; 6,605,057; 5,292,331;5,674,278; 5,879,382; 6,344,053; 5,423,851; 6,007,575; 5,501,759;5,674,208; 5,843,032; 5,961,765; 6,027,477; 6,319,228; 6,471,673;6,190,358; 6,605,057; 6,858,037; 7,001,358; 5,156,594; 5,217,482;5,395,334; 5,702,439; 5,501,759; 5,674,208; 5,843,032; 5,961,765;6,027,477; 6,319,228; 6,471,673; 5,759,192; 6,527,789; 5,147,302;5,342,307; 6,290,485; 6,352,551; 6,402,778; 6,488,694; 6,511,505;6,613,073; 6,582,458; 5,820,594; 5,824,173; 5,538,510; 4,323,071;4,762,129; 4,846,186; 5,156,594; 5,217,482; 5,395,334; 5,156,594;4,323,071; 5,040,548; 5,061,273; 5,451,233; 5,496,346; 5,496,275;5,496,346; 5,040,548; 5,061,273; 5,451,233; 5,496,346; 4,596,563;5,040,548; 5,061,273; 5,350,395; 5,451,233; 5,445,625; 6,083,213;6,475,195; 5,421,955; 5,514,154; 5,603,721; 5,292,331; 5,674,278;5,879,382; 6,344,053; 6,238,415; 5,421,955; 5,514,154; and 5,603,721.

The compounds of the invention may be administered in dosages asdescribed herein (see, e.g., Compositions). It is known in the art thatdue to intersubject variability in compound pharmacokinetics,individualization of dosing regimen is necessary for optimal therapy.Dosing for a compound of the invention may be found by routineexperimentation.

When a compound of the invention, is administered in a composition thatcomprises one or more agents, and the agent has a shorter half-life thanthe compound of the invention unit dose forms of the agent and thecompound of the invention may be adjusted accordingly. See e.g.,Compositions.

The subject pharmaceutical composition may, for example, be in a formsuitable for oral administration as a tablet, capsule, pill, powder,sustained release formulations, solution, suspension, for parenteralinjection as a sterile solution, suspension or emulsion, for topicaladministration as an ointment or cream or for rectal administration as asuppository. The pharmaceutical composition may be in unit dosage formssuitable for single administration of precise dosages. Thepharmaceutical composition will include a conventional pharmaceuticalcarrier or excipient and a compound according to the invention as anactive ingredient. In addition, it may include other medicinal orpharmaceutical agents, carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compound in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

The activity of the compounds of the present invention may be determinedby the following procedure, as well as the procedure described in theexamples below. N-terminal 6 His-tagged, constitutively active kinase isexpressed in E. coli and protein is purified by conventional methods(Ahn et al. Science 1994, 265, 966-970). The activity of the kinase isassessed by measuring the incorporation of γ-³³P-phosphate fromγ-³³P-ATP onto N-terminal His tagged substrate, which is expressed in E.coli and is purified by conventional methods, in the presence of thekinase. The assay is carried out in 96-well polypropylene plate. Theincubation mixture (100, μL) comprises of 25 mM Hepes, pH 7.4, 10 mMMgCl₂, 5 mM β-glycerolphosphate, 100 μM Na-orthovanadate, 5 mM DTT, 5 nMkinase, and 1 μM substrate. Inhibitors are suspended in DMSO, and allreactions, including controls are performed at a final concentration of1% DMSO. Reactions are initiated by the addition of 10 μM ATP (with 0.5μCi γ-³³P-ATP/well) and incubated at ambient temperature for 45 minutes.Equal volume of 25% TCA is added to stop the reaction and precipitatethe proteins. Precipitated proteins are trapped onto glass fiber Bfilterplates, and excess labeled ATP washed off using a Tomtec MACH IIIharvestor. Plates are allowed to air-dry prior to adding 30 μL/well ofPackard Microscint 20, and plates are counted using a Packard TopCount.

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

EXAMPLES Example 1 Expression and Inhibition Assays of p110α/p85α,p110β/p85α, p110δ/p85α, and p110γ

Class I PI3-Ks can be either purchased (p110α/p85α, p110β/p85α,p110δ/p85α from Upstate, and p110γ from Sigma) or expressed aspreviously described (Knight et al., 2004). IC50 values are measuredusing either a standard TLC assay for lipid kinase activity (describedbelow) or a high-throughput membrane capture assay. Kinase reactions areperformed by preparing a reaction mixture containing kinase, inhibitor(2% DMSO final concentration), buffer (25 mM HEPES, pH 7.4, 10 mMMgCl2), and freshly sonicated phosphatidylinositol (100 μg/ml).Reactions are initiated by the addition of ATP containing 10 μCi ofγ-32P-ATP to a final concentration 10 or 100 μM and allowed to proceedfor 5 minutes at room temperature. For TLC analysis, reactions are thenterminated by the addition of 105 l 1N HCl followed by 160 μl CHCl3:MeOH(1:1). The biphasic mixture is vortexed, briefly centrifuged, and theorganic phase is transferred to a new tube using a gel loading pipettetip precoated with CHCl₃. This extract is spotted on TLC plates anddeveloped for 3-4 hours in a 65:35 solution of n-propanol:1M aceticacid. The TLC plates are then dried, exposed to a phosphorimager screen(Storm, Amersham), and quantitated. For each compound, kinase activityis measured at 10-12 inhibitor concentrations representing two-folddilutions from the highest concentration tested (typically, 200 μM). Forcompounds showing significant activity, IC50 determinations are repeatedtwo to four times, and the reported value is the average of theseindependent measurements.

Other commercial kits or systems for assaying PI3-K activities areavailable. The commercially available kits or systems can be used toscreen for inhibitors and/or agonists of PI3-Ks including but notlimited to PI 3-Kinase α, β, δ, and γ. Anr exemplary system isPI3-Kinase (human) HTRF™ Assay from Upstate. The assay can be carriedout according to the procedures suggested by the manufacturer. Briefly,the assay is a time resolved FRET assay that indirectly measures PIP3product formed by the activity of a PI3-K. The kinase reaction isperformed in a microtitre plate (e.g., a 384 well microtitre plate). Thetotal reaction volume is approximately 20 ul per well. In the firststep, each well receives 2 ul of test compound in 20% dimethylsulphoxideresulting in a 2% DMSO final concentration. Next, approximately 14.5 ulof a kinase/PIP2 mixture (diluted in 1× reaction buffer) is added perwell for a final concentration of 0.25-0.3 ug/ml kinase and 10 uM PIP2.The plate is sealed and incubated for 15 minutes at room temperature. Tostart the reaction, 3.5 ul of ATP (diluted in 1× reaction buffer) isadded per well for a final concentration of 10 uM ATP. The plate issealed and incubated for 1 hour at room temperature. The reaction isstopped by adding 5 ul of Stop Solution per well and then 5 ul ofDetection Mix is added per well. The plate is sealed, incubated for 1hour at room temperature, and then read on an appropriate plate reader.Data is analyzed and IC50s are generated using GraphPad Prism 5.

Example 2 Expression and Inhibition Assays of Abl

The compounds described herein can be assayed in triplicate againstrecombinant full-length Abl or Abl (T315I) (Upstate) in an assaycontaining 25 mM HEPES, pH 7.4, 10 mM MgCl2, 200 μM ATP (2.5 Ci ofγ-32P-ATP), and 0.5 mg/mL BSA. The optimized Abl peptide substrateEAIYAAPFAKKK is used as phosphoacceptor (200 μM). Reactions areterminated by spotting onto phosphocellulose sheets, which are washedwith 0.5% phosphoric acid (approximately 6 times, 5-10 minutes each).Sheets are dried and the transferred radioactivity quantitated byphosphorimaging.

Example 3 Expression and Inhibition Assays of Hck

The compounds described herein can be assayed in triplicate againstrecombinant full-length Hck in an assay containing 25 mM HEPES, pH 7.4,10 mM MgCl2, 200 μM ATP (2.5 μCi of γ-32P-ATP), and 0.5 mg/mL BSA. Theoptimized Src family kinase peptide substrate EIYGEFKKK is used asphosphoacceptor (200 μM). Reactions are terminated by spotting ontophosphocellulose sheets, which are washed with 0.5% phosphoric acid(approximately 6 times, 5-10 minutes each). Sheets are dried and thetransferred radioactivity quantitated by phosphorimaging.

Example 4 Expression and Inhibition Assays of Inulsin Receptor (IR)

The compounds described herein can be assayed in triplicate againstrecombinant insulin receptor kinase domain (Upstate) in an assaycontaining 25 mM HEPES, pH 7.4, 10 mM MgCl2, 10 mM MnCl2, 200 pM ATP(2.5 μCi of γ-32P-ATP), and 0.5 mg/mL BSA. Poly E-Y (Sigma; 2 mg/mL) isused as a substrate. Reactions are terminated by spotting ontonitrocellulose, which is washed with 1M NaCl/1% phosphoric acid(approximately 6 times, 5-10 minutes each). Sheets are dried and thetransferred radioactivity quantitated by phosphorimaging.

Example 5 Expression and Inhibition Assays of Src

The compounds described herein can be assayed in triplicate againstrecombinant full-length Src or Src (T338I) in an assay containing 25 mMHEPES, pH 7.4, 10 mM MgCl2, 200 μM ATP (2.5 μCi of γ-32P-ATP), and 0.5mg/mL BSA. The optimized Src family kinase peptide substrate EIYGEFKKKis used as phosphoacceptor (200 μM). Reactions are terminated byspotting onto phosphocellulose sheets, which are washed with 0.5%phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets weredried and the transferred radioactivity quantitated by phosphorimaging.

Example 6 Expression and Inhibition Assays of DNA-PK (DNAK)

DNA-PK can be purchased from Promega and assayed using the DNA-PK AssaySystem (Promega) according to the manufacturer's instructions.

Example 7 Expression and Inhibition Assays mTOR

The compounds described herein can be tested against recombinant mTOR(Invitrogen) in an assay containing 50 mM HEPES, pH 7.5, 1 mM EGTA, 10mM MgCl2, 2.5 mM, 0.01% Tween, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3μg/mL BSA. Rat recombinant PHAS-1/4EBP1 (Calbiochem; 2 mg/mL) is used asa substrate. Reactions are terminated by spotting onto nitrocellulose,which is washed with 1M NaCl/1% phosphoric acid (approximately 6 times,5-10 minutes each). Sheets are dried and the transferred radioactivityquantitated by phosphorimaging.

Other kits or systems for assaying mTOR activity are commerciallyavailable. For instance, one can use Invitrogen's LanthaScreen™ Kinaseassay to test the inhibitors of mTOR disclosed herein. This assay is atime resolved FRET platform that measures the phosphorylation of GFPlabeled 4EBP 1 by mTOR kinase. The kinase reaction is performed in awhite 384 well microtitre plate. The total reaction volume is 20 ul perwell and the reaction buffer composition is 50 mM HEPES pH7.5, 0.01%Polysorbate 20, 1 mM EGTA, 10 mM MnCl2, and 2 mM DTT. In the first step,each well receives 2 ul of test compound in 20% dimethylsulphoxideresulting in a 2% DMSO final concentration. Next, 8 ul of mTOR dilutedin reaction buffer is added per well for a 60 ng/ml final concentration.To start the reaction, 10 ul of an ATP/GFP-4EBP1 mixture (diluted inreaction buffer) is added per well for a final concentration of 10 uMATP and 0.5 uM GFP-4EBP 1. The plate is sealed and incubated for 1 hourat room temperature. The reaction is stopped by adding 10 ul per well ofa Tb-anti-pT46 4EBP 1 antibody/EDTA mixture (diluted in TR-FRET buffer)for a final concentration of 1.3 nM antibody and 6.7 mM EDTA. The plateis sealed, incubated for 1 hour at room temperature, and then read on aplate reader set up for LanthaScreen™ TR-FRET. Data is analyzed andIC50s are generated using GraphPad Prism 5.

Example 8 Expression and Inhibition Assays of Vascular EndothelialGrowth Receptor

The compounds described herein can be tested against recombinant KDRreceptor kinase domain (Invitrogen) in an assay containing 25 mM HEPES,pH 7.4, 10 mM MgCl2, 0.1% BME, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3μg/mL BSA. Poly E-Y (Sigma; 2 mg/mL) is used as a substrate. Reactionsare terminated by spotting onto nitrocellulose, which is washed with 1MNaCl/1% phosphoric acid (approximately 6 times, 5-10 minutes each).Sheets are dried and the transferred radioactivity quantitated byphosphorimaging.

Example 9 Expression and Inhibition Assays of Ephrin Receptor B4 (EphB4)

The compounds described herein can be tested against recombinant Ephrinreceptor B4 kinase domain (Invitrogen) in an assay containing 25 mMHEPES, pH 7.4, 10 mM MgCl2, 0.1% BME, 10 μM ATP (2.5 μCi of μ-32P-ATP),and 3 μg/mL BSA. Poly E-Y (Sigma; 2 mg/mL) is used as a substrate.Reactions are terminated by spotting onto nitrocellulose, which iswashed with 1M NaCl/1% phosphoric acid (approximately 6 times, 5-10minutes each). Sheets are dried and the transferred radioactivityquantitated by phosphorimaging.

Example 10 Expression and Inhibition Assays of Epidermal Growth FactorReceptor (EGFR)

The compounds described herein can be tested against recombinant EGFreceptor kinase domain (Invitrogen) in an assay containing 25 mM HEPES,pH 7.4, 10 mM MgCl2, 0.1% BME, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3μg/mL BSA. Poly E-Y (Sigma; 2 mg/mL) is used as a substrate. Reactionsare terminated by spotting onto nitrocellulose, which is washed with 1MNaCl/1% phosphoric acid (approximately 6 times, 5-10 minutes each).Sheets are dried and the transferred radioactivity quantitated byphosphorimaging.

Example 11 Expression and Inhibition Assays of KIT Assay

The compounds described herein can be tested against recombinant KITkinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4,10 mM MgCl2, 1 mM DTT, 10 mM MnCl2, 10 μM ATP (2.5 μCi of μ-32P-ATP),and 3 μg/mL BSA. Poly E-Y (Sigma; 2 mg/mL) is used as a substrate.Reactions are terminated by spotting onto nitrocellulose, which iswashed with 1M NaCl/1% phosphoric acid (approximately 6 times, 5-10minutes each). Sheets are dried and the transferred radioactivityquantitated by phosphorimaging.

Example 12 Expression and Inhibition Assays of RET

The compounds described herein can be tested against recombinant RETkinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4,10 mM MgCl2, 2.5 mM DTT, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3 μg/mLBSA. The optimized Abl peptide substrate EAIYAAPFAKKK is used asphosphoacceptor (200 μM). Reactions are terminated by spotting ontophosphocellulose sheets, which are washed with 0.5% phosphoric acid(approximately 6 times, 5-10 minutes each). Sheets are dried and thetransferred radioactivity quantitated by phosphorimaging.

Example 13 Expression and Inhibition Assays of Platelet Derived GrowthFactor Receptor (PDGFR)

The compounds described herein can be tested against recombinant PDGreceptor kinase domain (Invitrogen) in an assay containing 25 mM HEPES,pH 7.4, 10 mM MgCl2, 2.5 mM DTT, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3μg/mL BSA. The optimized Abl peptide substrate EAIYAAPFAKKK is used asphosphoacceptor (200 μM). Reactions are terminated by spotting ontophosphocellulose sheets, which are washed with 0.5% phosphoric acid(approximately 6 times, 5-10 minutes each). Sheets are dried and thetransferred radioactivity quantitated by phosphorimaging.

Example 14 Expression and Inhibition Assays of FMS-Related TyrosineKinase 3 (FLT-3)

The compounds described herein can be tested against recombinant FLT-3kinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4,10 mM MgCl2, 2.5 mM DTT, 10 μM ATP (2.5 μCi of p-32P-ATP), and 3 μg/mLBSA. The optimized Abl peptide substrate EAIYAAPFAKKK is used asphosphoacceptor (200 μM). Reactions are terminated by spotting ontophosphocellulose sheets, which are washed with 0.5% phosphoric acid(approximately 6 times, 5-10 minutes each). Sheets are dried and thetransferred radioactivity quantitated by phosphorimaging.

Example 15 Expression and Inhibition Assays of TEK Receptor TyrosineKinase (TIE2)

The compounds described herein can be tested against recombinant TIE2kinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4,10 mM MgCl2, 2 mM DTT, 10 mM MnCl2, 10 μM ATP (2.5 μCi of μ-32P-ATP),and 3 Rtg/mL BSA. Poly E-Y (Sigma; 2 mg/mL) is used as a substrate.Reactions are terminated by spotting onto nitrocellulose, which iswashed with IM NaCl/1% phosphoric acid (approximately 6 times, 5-10minutes each). Sheets are dried and the transferred radioactivityquantitated by phosphorimaging.

Example 16 B Cell Activation and Proliferation Assay

The ability of one or more subject compounds to inhibit B cellactivation and proliferation is determined according to standardprocedures known in the art. For example, an in vitro cellularproliferation assay is established that measures the metabolic activityof live cells. The assay is performed in a 96 well microtiter plateusing Alamar Blue reduction. Balb/c splenic B cells are purified over aFicoll-Paque™ PLUS gradient followed by magnetic cell separation using aMACS B cell Isolation Kit (Miletenyi). Cells are plated in 90 ul at50,000 cells/well in B Cell Media (RPMI+10% FBS+Penn/Strep+50 uM bME+5mM HEPES). A compound disclosed herein is diluted in B Cell Media andadded in a 10 ul volume. Plates are incubated for 30 min at 37 C and 5%CO₂ (0.2% DMSO final concentration). A 50 ul B cell stimulation cocktailis then added containing either 10 ug/ml LPS or 5 ug/ml F(ab′)2 Donkeyanti-mouse IgM plus 2 ng/ml recombinant mouse IL4 in B Cell Media.Plates are incubated for 72 hours at 37° C. and 5% CO₂. A volume of 15uL of Alamar Blue reagent is added to each well and plates are incubatedfor 5 hours at 37 C and 5% CO₂. Alamar Blue fluoresce is read at560Ex/590Em, and IC50 or EC50 values are calculated using GraphPad Prism5.

Example 17 Tumor Cell Line Proliferation Assay

The ability of one or more subject compounds to inhibit tumor cell lineproliferation is determined according to standard procedures known inthe art. For instance, an in vitro cellular proliferation assay can beperformed to measure the metabolic activity of live cells. The assay isperformed in a 96 well microtiter plate using Alamar Blue reduction.Human tumor cell lines are obtained from ATCC (e.g., MCF7, U-87 MG,MDA-MB-468, PC-3), grown to confluency in T75 flasks, trypsinized with0.25% trypsin, washed one time with Tumor Cell Media (DMEM+10% FBS), andplated in 90 ul at 5,000 cells/well in Tumor Cell Media. A compounddisclosed herein is diluted in Tumor Cell Media and added in a 10 ulvolume. Plates are incubated for 72 hours at 37 C and 5% CO₂. A volumeof 10 uL of Alamar Blue reagent is added to each well and plates areincubated for 3 hours at 37 C and 5% CO₂. Alamar Blue fluoresce is readat 560Ex/590Em, and IC50 values are calculated using GraphPad Prism 5.

Example 18 Antitumor Activity in Vivo

The compounds described herein can be evaluated in a panel of human andmurine tumor models.

Paclitaxel-Refractory Tumor Models

-   -   1. Clinically-Derived Ovarian Carcinoma Model.

This tumor model is established from a tumor biopsy of an ovarian cancerpatient. Tumor biopsy is taken from the patient.

The compounds described herein are administered to nude mice bearingstaged tumors using an every 2 days×5 schedule.

-   -   2. A2780Tax Human Ovarian Carcinoma Xenograft (Mutated Tubulin).

A2780Tax is a paclitaxel-resistant human ovarian carcinoma model. It isderived from the sensitive parent A2780 line by co-incubation of cellswith paclitaxel and verapamil, an MDR-reversal agent. Its resistancemechanism has been shown to be non-MDR related and is attributed to amutation in the gene encoding the beta-tubulin protein.

The compounds described herein can be administered to mice bearingstaged tumors on an every 2 days×5 schedule.

-   -   3. HCT116/VM46 Human Colon Carcinoma Xenograft (Multi-Drug        Resistant).

HCT116/VM46 is an MDR-resistant colon carcinoma developed from thesensitive HCT 116 parent line. In vivo, grown in nude mice, HCT116/VM46has consistently demonstrated high resistance to paclitaxel.

The compounds described herein can be administered to mice bearingstaged tumors on an every 2 days×5 schedule.

-   -   5. M5076 Murine Sarcoma Model

M5076 is a mouse fibrosarcoma that is inherently refractory topaclitaxel in vivo.

The compounds described herein can be administered to mice bearingstaged tumors on an every 2 days×5 schedule.

One or more compounds of the invention can be used in combination othertherapeutic agents in vivo in the multidrug resistant human coloncarcinoma xenografts HCT/VM46 or any other model known in the artincluding those described herein.

Example 19 Microsome Stability Assay

The stability of one or more subject compounds is determined accordingto standard procedures known in the art. For example, stability of oneor more subject compounds is established by an in vitro assay.

In particular, an in vitro microsome stability assay is established thatmeasures stability of one or more subject compounds when reacting withmouse, rat or human microsomes from liver. The microsome reaction withcompounds is performed in 1.5 mL Eppendorf tube. Each tube contains 0.1μL of 10.0 mg/ml NADPH; 75 μL of 20.0 mg/ml mouse, rat or human livermicrosome; 0.4 μL of 0.2 M phosphate buffer, and 425 μL of ddH₂O.Negative control (without NADPH) tube contains 75 μL of 20.0 mg/mlmouse, rat or human liver microsome; 0.4 μL of 0.2 M phosphate buffer,and 525 μL of ddH₂O. The reaction is started by adding 1.0 μL of 10.0 mMtested compound. The reaction tubes are incubated at 37° C. 100 μLsample is collected into new Eppendorf tube containing 300 μL coldMethanol at 0, 5, 10, 15, 30 and 60 minutes of reaction. Samples arecentrifuged at 15,000 rpm to remove protein. Supernatant of centrifugedsample is transferred to new tube. Concentration of stable compoundafter reaction with microsome in the supernatant is measured by LiquidChromatography/Mass Spectrometry (LC-MS).

Example 20 Plasma Stability Assay

The stability of one or more subject compounds in plasma is determinedaccording to standard procedures known in the art. See, e.g., RapidCommun. Mass Spectrom., 10: 1019-1026. The following procedure is anHPLC-MS/MS assay using human plasma; other species including monkey,dog, rat, and mouse are also available. Frozen, heparinized human plasmais thawed in a cold water bath and spun for 10 minutes at 2000 rpm at 4°C. prior to use. A subject compound is added from a 400 μM stocksolution to an aliquot of pre-warmed plasma to give a final assay volumeof 400 μL (or 800 μL for half-life determination), containing 5 μM testcompound and 0.5% DMSO. Reactions are incubated, with shaking, for 0minutes and 60 minutes at 37° C., or for 0, 15, 30, 45 and 60 minutes at37 C for half life determination. Reactions are stopped by transferring50 μL of the incubation mixture to 200 μL of ice-cold acetonitrile andmixed by shaking for 5 minutes. The samples are centrifuged at 6000×gfor 15 minutes at 4° C. and 120 μL of supernatant removed into cleantubes. The samples are then evaporated to dryness and submitted foranalysis by HPLC-MS/MS.

Where desired, one or more control or reference compounds (5 μM) aretested simultaneously with the test compounds: one compound,propoxycaine, with low plasma stability and another compound,propantheline, with intermediate plasma stability.

Samples are reconstituted in acetonitrile/methanol/water (1/1/2, v/v/v)and analyzed via (RP)HPLC-MS/MS using selected reaction monitoring(SRM). The HPLC conditions consist of a binary LC pump with autosampler,a mixed-mode, C12, 2×20 mm column, and a gradient program. Peak areascorresponding to the analytes are recorded by HPLC-MS/MS. The ratio ofthe parent compound remaining after 60 minutes relative to the amountremaining at time zero, expressed as percent, is reported as plasmastability. In case of half-life determination, the half-life isestimated from the slope of the initial linear range of the logarithmiccurve of compound remaining (%) vs. time, assuming first order kinetics.

Example 21 Chemical Stability

The chemical stability of one or more subject compounds is determinedaccording to standard procedures known in the art. The following detailsan exemplary procedure for ascertaining chemical stability of a subjectcompound. The default buffer used for the chemical stability assay isphosphate-buffered saline (PBS) at pH 7.4; other suitable buffers can beused. A subject compound is added from a 100 M stock solution to analiquot of PBS (in duplicate) to give a final assay volume of 400 μL,containing 5 μM test compound and 1% DMSO (for half-life determination atotal sample volume of 700 μL is prepared). Reactions are incubated,with shaking, for 0 minutes and 24 hours at 37° C.; for half-lifedetermination samples are incubated for 0, 2, 4, 6, and 24 hours.Reactions are stopped by adding immediately 100 gtL of the incubationmixture to 100 μL of acetonitrile and vortexing for 5 minutes. Thesamples are then stored at −20° C. until analysis by HPLC-MS/MS. Wheredesired, a control compound or a reference compound such as chlorambucil(5 μM) is tested simultaneously with a subject compound of interest, asthis compound is largely hydrolyzed over the course of 24 hours. Samplesare analyzed via (RP)HPLC-MS/MS using selected reaction monitoring(SRM). The HPLC conditions consist of a binary LC pump with autosampler,a mixed-mode, C12, 2×20 mm column, and a gradient program. Peak areascorresponding to the analytes are recorded by HPLC-MS/MS. The ratio ofthe parent compound remaining after 24 hours relative to the amountremaining at time zero, expressed as percent, is reported as chemicalstability. In case of half-life determination, the half-life isestimated from the slope of the initial linear range of the logarithmiccurve of compound remaining (%) vs. time, assuming first order kinetics.

Example 22 Akt Kinase Assay

Cells comprising components of the Akt/mTOR pathway, including but notlimited to L6 myoblasts, B-ALL cells, B-cells, T-cells, leukemia cells,bone marrow cells, p190 transduced cells, philladelphia chromosomepositive cells (Ph+), and mouse embryonic fibroblasts, are typicallygrown in cell growth media such as DMEM supplemented with fetal bovineserum and/or antibiotics, and grown to confluency.

In order to compare the effect of one or more compounds disclosed hereinon Akt activation, said cells are serum starved overnight and incubatedwith one or more compounds disclosed herein or about 0.1% DMSO forapproximately 1 minute to about 1 hour prior to stimulation with insulin(e.g. 100 nM) for about 1 minutes to about 1 hour. Cells are lysed byscraping into ice cold lysis buffer containing detergents such as sodiumdodecyl sulfate and protease inhibitors (e.g., PMSF). After contactingcells with lysis buffer, the solution is briefly sonicated, cleared bycentrifugation, resolved by SDS-PAGE, transferred to nitrocellulose orPVDF and immunoblotted using antibodies to phospho-Akt S473, phospho-AktT308, Akt, and β-actin (Cell Signaling Technologies).

The results demonstrate that one or more compounds of the presentdisclosure inhibit insulin stimulated phosphorylation of Akt at S473.Alternatively, some compounds disclosed herein additionally inhibitinsulin stimulated phosphorylation of Akt at T308. Such class ofcompounds can inhibit Akt more effectively than rapamycin and may beindicative of mTORC2 inhibitors or inhibitors of upstream kinases suchas PI3K or Akt.

Example 23 Kinase Signaling in Blood

PI3K/Akt/mTor signaling is measured in blood cells using the phosflowmethod (Methods Enzymol. 2007; 434:131-54). The advantage of this methodis that it is by nature a single cell assay so that cellularheterogeneity can be detected rather than population averages. Thisallows concurrent distinction of signaling states in differentpopulations defined by other markers. Phosflow is also highlyquantitative. To test the effects of one or more compounds disclosedherein, unfractionated splenocytes, or peripheral blood mononuclearcells are stimulated with anti-CD3 to initiate T-cell receptorsignaling. The cells are then fixed and stained for surface markers andintracellular phosphoproteins. It is expected that inhibitors disclosedherein inhibit anti-CD3 mediated phosphorylation of Akt-S473 and S6,whereas rapamycin inhibits S6 phosphorylation and enhances Aktphosphorylation under the conditions tested.

Similarly, aliquots of whole blood are incubated for 15 minutes withvehicle (e.g. 0.1% DMSO) or kinase inhibitors at various concentrations,before addition of stimuli to crosslink the T cell receptor (TCR)(anti-CD3 with secondary antibody) or the B cell receptor (BCR) usinganti-kappa light chain antibody (Fab′2 fragments). After approximately 5and 15 minutes, samples are fixed (e.g. with cold 4% paraformaldehyde)and used for phosflow. Surface staining is used to distinguish T and Bcells using antibodies directed to cell surface markers that are knownto the art. The level of phosphrylation of kinase substrates such as Aktand S6 are then measured by incubating the fixed cells with labeledantibodies specific to the phosphorylated isoforms of these proteins.The population of cells are then analyzed by flow cytometry.

Example 24 Colony Formation Assay

Murine bone marrow cells freshly transformed with a p190 BCR-Ablretrovirus (herein referred to as p190 transduced cells) are plated inthe presence of various drug combinations in M3630 methylcellulose mediafor about 7 days with recombinant human IL-7 in about 30% serum, and thenumber of colonies formed is counted by visual examination under amicroscope.

Alternatively, human peripheral blood mononuclear cells are obtainedfrom Philadelphia chromosome positive (Ph+) and negative (Ph−) patientsupon initial diagnosis or relapse. Live cells are isolated and enrichedfor CD19+CD34+ B cell progenitors. After overnight liquid culture, cellsare plated in methocult GF+H4435, Stem Cell Tehcnologies) supplementedwith cytokines (IL-3, IL-6, IL-7, G-CSF, GM-CSF, CF, Flt3 ligand, anderythropoietin) and various concentrations of known chemotherapeuticagents in combination with either compounds of the present disclosure.Colonies are counted by microscopy 12-14 days later. This method can beused to test for evidence of additive or synergistic activity.

Example 25 In Vivo Effect of Kinase Inhibitors on Leukemic Cells

Female recipient mice are lethally irradiated from a γ source in twodoses about 4 hr apart, with approximately 5 Gy each. About 1 hr afterthe second radiation dose, mice are injected i.v. with about 1×10⁶leukemic cells (e.g. Ph+ human or murine cells, or p190 transduced bonemarrow cells). These cells are administered together with aradioprotective dose of about 5×10⁶ normal bone marrow cells from 3-5week old donor mice. Recipients are given antibiotics in the water andmonitored daily. Mice who become sick after about 14 days are euthanizedand lymphoid organs are harvested for analysis. Kinase inhibitortreatment begins about 10 days after leukemic cell injection andcontinues daily until the mice become sick or a maximum of approximately35 days post-transplant. Inhibitors are given by oral lavage.

Peripheral blood cells are collected approximately on day 10(pre-treatment) and upon euthanization (post treatment), contacted withlabled anti-hCD4 antibodies and counted by flow cytometry. This methodcan be used to demonstrate that the synergistic effect of one or morecompouns disclosed herein in combination with known chemotherapeuticagents significantly reduce leukemic blood cell counts as compared totreatment with known chemotherapeutic agents (e.g. Gleevac) alone underthe conditions tested.

Example 26 Treatment of Lupus Disease Model Mice

Mice lacking the inhibitory receptor FcγRIIb that opposes PI3K signalingin B cells develop lupus with high penetrance. FcγRIIb knockout mice(R²KO, Jackson Labs) are considered a valid model of the human diseaseas some lupus patients show decreased expression or function of FcγRIIb(S. Bolland and J. V. Ravtech 2000. Immunity 12:277-285).

The R²KO mice develop lupus-like disease with anti-nuclear antibodies,glomerulonephritis and proteinurea within about 4-6 months of age. Forthese experiments, the rapamycin analogue RAD001 (available from LCLaboratories) is used as a benchmark compound, and administered orally.This compound has been shown to ameliorate lupus symptoms in theB6.Slelz.Sle3z model (T. Wu et al. J. Clin Invest. 117:2186-2196).

Lupus disease model mice such as R²KO, BXSB or MLR/lpr are treated atabout 2 months old, approximately for about two months. Mice are givendoses of: vehicle, RAD001 at about 10 mg/kg, or compounds disclosedherein at approximately 1 mg/kg to about 500 mg/kg. Blood and urinesamples are obtained at approximately throughout the testing period, andtested for antinuclear antibodies (in dilutions of serum) or proteinconcentration (in urine). Serum is also tested for anti-ssDNA andanti-dsDNA antibodies by ELISA. Animals are euthanized at day 60 andtissues harvested for measuring spleen weight and kidney disease.Glomerulonephritis is assessed in kidney sections stained with H&E.Other animals are studied for about two months after cessation oftreatment, using the same endpoints.

This model established in the art can be employed to demonstrate thatthe kinase inhibitors disclosed herein can suppress or delay the onsetof lupus symptoms in lupus disease model mice.

Example 27 Murine Bone Marrow Transplant Assay

Female recipient mice are lethally irradiated from a γ ray source. About1 hr after the radiation dose, mice are injected with about 1×106leukemic cells from early passage p190 transduced cultures (e.g. asdescribed in Cancer Genet Cytogenet. 2005 August; 161(1):51-6). Thesecells are administered together with a radioprotective dose ofapproximately 5×106 normal bone marrow cells from 3-5 wk old donor mice.Recipients are given antibiotics in the water and monitored daily. Micewho become sick after about 14 days are euthanized and lymphoid organsharvested for flow cytometry and/or magnetic enrichment. Treatmentbegins on approximately day 10 and continues daily until mice becomesick, or after a maximum of about 35 days post-transplant. Drugs aregiven by oral gavage (p.o.). In a pilot experiment a dose ofchemotherapeutic that is not curative but delays leukemia onset by aboutone week or less is identified; controls are vehicle-treated or treatedwith chemotherapeutic agent, previously shown to delay but not cureleukemogenesis in this model (e.g. imatinib at about 70 mg/kg twicedaily). For the first phase p190 cells that express eGFP are used, andpostmortem analysis is limited to enumeration of the percentage ofleukemic cells in bone marrow, spleen and lymph node (LN) by flowcytometry. In the second phase, p190 cells that express a tailless formof human CD4 are used and the postmortem analysis includes magneticsorting of hCD4+ cells from spleen followed by immunoblot analysis ofkey signaling endpoints: p Akt-T308 and S473; pS6 and p4EBP-1. Ascontrols for immunoblot detection, sorted cells are incubated in thepresence or absence of kinase inhibitors of the present disclosureinhibitors before lysis. Optionally, “phosflow” is used to detect pAkt-S473 and pS6-S235/236 in hCD4-gated cells without prior sorting.These signaling studies are particularly useful if, for example,drug-treated mice have not developed clinical leukemia at the 35 daytime point. Kaplan-Meier plots of survival are generated and statisticalanalysis done according to methods known in the art. Results from p190cells are analyzed separated as well as cumulatively.

Samples of peripheral blood (100-200 μl) are obtained weekly from allmice, starting on day 10 immediately prior to commencing treatment.Plasma is used for measuring drug concentrations, and cells are analyzedfor leukemia markers (eGFP or hCD4) and signaling biomarkers asdescribed herein.

This general assay known in the art may be used to demonstrate thateffective therapeutic doses of the compounds disclosed herein can beused for inhibiting the proliferation of leukemic cells.

What is claimed is:
 1. A compound of formula I-H:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is hydrogen;n is an integer from 0 to 2; L¹ is a bond; R³ is hydrogen; R⁴ and R⁵ aretaken together to form a fused phenyl ring, wherein the phenyl ring isunsubstituted; z is 1, 2, or 3; each of R⁶ is independently hydrogen,halogen, —CN, —OR¹⁰, —S(O)_(n)R¹¹, —NR¹²R¹³, —C(O)R¹⁴, alkyl, alkenyl,alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each of R⁷ and R⁸ is independently hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocyclyalkyl, or R⁷ and R⁸ taken together form acycloalkyl, heterocycloalkyl or aryl ring; R⁹ is aryl or —NR¹²R¹³,wherein R¹² and R¹³ are taken together to form a 5, 6, 7, or 8 memberedring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ringheteroatoms selected from N, S, or O in addition to the nitrogen atom of—NR¹²R¹³; and further wherein the 5, 6, 7, or 8 membered ring isoptionally substituted; each R¹⁰ is independently hydrogen, —C(O)R¹⁵,alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R¹¹ is independently —NR¹⁶R¹⁷, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; each R¹² is independentlyhydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; each R¹³ is independently hydrogen, —S(O)_(n)R¹⁸, —C(O)R¹⁹,alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;or R¹² and R¹³ are taken together to form a 5, 6, 7, or 8 membered ring,wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ringheteroatoms selected from N, S, or O in addition to the nitrogen atom of—NR¹²R¹³; and further wherein the 5, 6, 7, or 8 membered ring isoptionally substituted; each R¹⁴ is independently —NR²⁰R²¹, hydrogen,alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R¹⁵ is independently —NR²²R²³, hydrogen, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of R¹⁶ and R¹⁷is independently hydrogen, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; or R¹⁶ and R¹⁷ are taken togetherto form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S,or O in addition to the nitrogen atom of —NR¹⁶R¹⁷; and further whereinthe 5, 6, 7, or 8 membered ring is optionally substituted; each R¹⁸ isindependently hydrogen, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; each R¹⁹ is independently—NR²⁴R²⁵, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,aryl, or heteroaryl; each of R²⁰ and R²¹ is independently hydrogen,alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,or R²⁰ and R²¹ are taken together to form a 5, 6, 7, or 8 membered ring,wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ringheteroatoms selected from N, S, or O in addition to the nitrogen atom of—NR²⁰R²¹; and further wherein the 5, 6, 7, or 8 membered ring isoptionally substituted; each R²² and R²³ are independently hydrogen,alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,or R²² and R²³ are taken together to form a 5, 6, 7, or 8 membered ring,wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ringheteroatoms selected from N, S, or O in addition to the nitrogen atom of—NR²²R²³; and further wherein the 5, 6, 7, or 8 membered ring isoptionally substituted; each R²⁴ and R²⁵ are independently hydrogen,alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,or R²⁴ and R²⁵ are taken together to form a 5, 6, 7, or 8 membered ring,wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ringheteroatoms selected from N, S, or O in addition to the nitrogen atom of—NR²⁴ R²⁵; and further wherein the 5, 6, 7, or 8 membered ring isoptionally substituted; and W is CR⁶ or N.
 2. The compound of claim 1,wherein z is
 1. 3. The compound of claim 1, wherein R⁷ is alkyl.
 4. Thecompound of claim 1, wherein R⁷ and R⁸ are hydrogen.
 5. The compound ofclaim 1, wherein R⁹ is aryl.
 6. The compound of claim 1, wherein R⁹ is—NR¹²R¹³, wherein R¹² and R¹³ are taken together to form a 5, 6, 7, or 8membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2or 3 ring heteroatoms selected from N, S, or O in addition to thenitrogen atom of —NR¹²R¹³; and further wherein the 5, 6, 7, or 8membered ring is optionally substituted.
 7. The compound of claim 1,wherein W is CR⁶.
 8. The compound of claim 7, wherein R⁶ is hydrogen. 9.The compound of claim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising a compound of claim 1 or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable excipient.